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Obtaining adequate surgical margin status in breast-conservation therapy: intraoperative ultrasound-guided resection versus specimen mammography

Obtaining adequate surgical margin status in breast-conservation therapy: intraoperative... Background and aim. The purpose of breast-conserving surgery (BCS) for women with cancer is to perform an oncological radical procedure with disease-free margins at the final histological assessment and with the best aesthetic result possible. Intraoperative resected specimen ultrasound and intraoperative resected specimen mammography may reduce the rates of positive margins and reexcision among patients undergoing conserving therapy. Our objective is to compare the two methods with the histopathological results for a preset cut off and asses which parameters can influence the positive margin status. Method. A prospective study was performed on 83 patients who underwent breast conservation surgery for early breast cancer (pT1-3a pN0-1 M0) between 2014 and 2016. After excision the specimen was oriented in the operating room by the surgeon. Metallic clips and threads were placed on margins: one clip and the long thread at 12 o’clock, two clips and the short threads at 9 o’clock. The next step was intraoperative ultrasound assessment of the specimen. For the margins under 2 mm we performed selective margin shaving, followed by mammography to identify and document the lesion and finally histopathological examination of the specimen with reporting the gross and microscopic margins. The positive margins required re-excision or boost of radiation at the posterior or anterior margins, depending on the case. Results. We set a cut-off at 2 mm. The sensitivity and specificity of the intraoperative margin assessment via the ultrasound method were 90.91% (95% CI 70.84-98.88%) and 67.21% (95% CI 54-78.69%) respectively. The sensitivity and specificity of the intraoperative margin assessment via the mammographic procedure were 45.45% (95% CI 24.39-67.79%) and 85.25% (95% CI 73.83-93.02%) respectively. There was positive correlation between the histopathological and intraoperative ultrasound exam (p=0.018) and negative correlation between the histopathological exam and the post-operative mammographic exam (p=0.68). We found a positive correlation between the positive margin status and age (<40), preoperative chemotherapy, intraductal carcinoma, inflammatory process around the tumor, and the immunohistochemical triple negative profile. Conclusions. According to our results, the intraoperative ultrasound of the breast specimen for a cutt-off at 2 mm can decrease the rates of margin positivity compared to the mammographic procedure and has the potential to diminish the number of subsequent undesired re-excisions. Keywords: breast-conserving surgery, intraoperative ultrasound, specimen mammography Manuscript received: 15.09.2017 Received in revised form: 01.12.2017 Accepted: 24.01.2018 Address for correspondence: sylvinho_46@yahoo.com Clujul Medical Vol. 91, No. 2, 2018: 197-202 197 Surgery Background and aims histopathological examination in order to obtain a negative Surgery continues to be the main pillar of breast margin status for a preset cut-off. The secondary objective cancer therapy nowadays. With the development and is to determine the parameters that can influence margin widespread of breast cancer diagnostic techniques, the status. addition of adjuvant therapy, the expansion of knowledge in the field of cancer biology have led in recent decades Methods to the narrowing of the operative act and the emergence Eligibility. An observational prospective study of a new concept: conservative surgery. As an alternative was performed on 83 patients who underwent breast to mastectomy, conservative surgery pursues two goals: conservation surgery (BCS) for early breast cancer (pT1-3a effective local oncology (radicality) and achieving the pN0-1 M0) between 2014 and 2016 in Tîrgu Mureş County best aesthetic result possible, with the main focus being Hospital, Department of General Surgery. The study was on the principle of radicalism [1,2]. Surgical treatment approved by the Ethics Committees of the Tîrgu Mureş for early stage breast cancer hasn’t always been breast County Hospital and of the University of Medicine and conservative. In 1894 William Halsted revolutionized his Pharmacy of Tîrgu Mureş. Pregnant women, patients with time with the radical mastectomy. Half a century later, in benign pathology at final histopathological assessment, 1948 Patey and Madden refined the procedure, introducing patients unable to receive anesthesia or those refusing the modified radical mastectomy [3,4,5]. Medicine evolved surgical treatment, were excluded. and paradigms shifted, making breast conservation therapy Clinical Protocol. During the operation, after the desired technique after the 1991 National Institute of excision, the specimen was oriented in the operating room Health Consensus on breast cancer, determined by the by the surgeon. Metallic clips and threads were placed on Veronessi and Fisher studies, a few years earlier [6,7,8]. the margins: one clip and the long thread at 12 o’clock, two The goal for patients with early breast cancer is to clips and the short threads at 9 o’clock. The next step was obtain negative margins at the final histological assessment intraoperative ultrasound assessment of the specimen, using [9,10]. Among the first trials to deal with this matter were Philips ClearVue 650 with the frequency linear transducer the ones published by Gustave Roussy Institute (1988), set at 12 MHz. The procedure was performed directly on Stanford University Medical Center (1972-1992) and the specimen after resection, without prior immersion START trial (1992-2002) [11,12,13]. The 2014 guidelines of the surgical piece in saline solution. Selective margin endorsed by SSO-ASTRO Consensus, advocate no ink on shavings were carried out for close margins (<2 mm) at tumor as the new margin requirement. This approach to the discretion of the surgeon and the new margins of the breast cancer has gained rapid followers around the world, additional resections were oriented by sutures. Afterwards being today a commonly recognized treatment method [14]. intraoperative resected specimen mammography was The current intra-operative trend is the simultaneous performed, and six radial distances from all margins use of diagnostic and therapeutic procedures, resulting in the (superior, inferior, lateral, medial, anterior and posterior) so-called ”theranostic” procedure in which intraoperative were recorded to identify and document the targeted lesion. ultrasonography plays an important role in assessing Finally, the specimens were evaluated by board certified marginal status and having the ability to differentiate pathologists who painted the six surfaces and reported normal tissue from benign or malignant changes [15,16,17]. the gross and microscopic margins. The new resection In 1988, Schwartz published a study using ultrasound as margins of the additional intraoperative resections were an alternative technique for detecting non-palpable breast also inked. The tissue specimen and additional resections tumors [18,19]. Since then, other studies have sought to were serially sectioned at 3- to 3-mm intervals and stained confirm the feasibility and safety of the impalpable and by hematoxylin and eosin. Reoperation was recommended palpable breast tumor method [20-24]. Another approach for any margin <2 mm at the pathology assessment. designed to achieve negative margins is mammography of Statistical analysis. The analysis was made on the the specimen. The accuracy of the method is determined by number of patients on whom the methods demonstrated its ability to provide information on the presence or absence evidence of tumor cells at least one resection margin or of microcalcifications, but also on parenchymal distortions very close to a margin (<2 mm). Subsequently the data [25,26,27]. Among the limitations of this technique are the was processed using Microsoft Office Excel 2010 tables. “pancake” phenomenon and the existence of an invasive Calculation of sensitivity and specificity were performed lobular carcinoma surrounded by dense tissue. The latter using MedCalc 17.4.4. The results were further compiled requires, according to the 2005 Consensus Statement using the GraphPad Prism 6 program. The correlation of issued by the American Society of Breast Surgeons, the use the different parameters required the application of tests of MRI over mammography [28,29]. such as: test T student for non-paired data, Fisher test, Chi The main aim of the study is the evaluation of square test. P values < 0.05 were considered statistically intraoperative ultrasonography and mammography of significant. the specimen excised according to the final result of the Clujul Medical Vol. 91, No. 2, 2018: 197-202 198 Original Research Results 70.84-98.88%) and specificity of 67.21 % (95% CI 54- The study group included 83 patients aged between 78.69%) in the evaluation of surgical pathology margins 33-89 years with the median age of 57.3. They were (Figure 1, Table I). Regarding the specimen mammography divided into 2 age subgroups: <40 years (n=10), ≥40 years margins with 2 mm cut-off, the sensibility and specificity (n=73). 74 (89%) patients had a tumor-free margin. Of were 45.45% (95% CI 24.39-67.79%) respectively 85.25% note, a tumor-free margin was defined as ‘no tumor on ink’. (95% CI 73.83-93.02%) (Figure 2, Table II). Specimen ultrasound (hypoechoic targeted mass found <2 The correlation between different parameters and mm from the edge) had a sensitivity of 90.91 % ( 95% CI the marginal status is exemplified in Table III. Figure 1. ROC Curve regarding the comparison of specimen Figure 2. ROC Curve regarding the comparison of specimen ultrasound margins with surgical pathology 2 mm cut-off. mammography margins with surgical pathology 2 mm cut off. Table I. Comparison of specimen ultrasound margins with surgical pathology (cut off=2 mm). Specimen ultrasound Surgical pathology positive Margins report negative Total Positive (<2 mm) 8 (true positive) 25 (false positive) 33 Negative (>2 mm) 1 (false negative) 49 (true negative) 50 Total 9 74 83 Table II. Comparison of specimen mammography margins with surgical pathology (cut off=2 mm). Specimen mammography Surgical pathology positive Margins report negative Total Positive (<2 mm) 4 (true positive) 11 (false positive) 15 Negative (>2 mm) 5 (false negative) 63 (true negative) 68 Total 9 74 83 Table III. The correlation between different parameters and the surgical margin status. Variable Applied Test P value Age: <40 or ≥40 P<0.01 Unpaired T test Tumor size <20 mm or >20 mm P=0.965 Preoperative chemotherapy: Yes/ No P=0.0302 Fisher test Histologic type: Ductal/lobular/others P=0.0406 Grade: 1/2/3 P=0.144 Microcalcifications: Present/Absent P=0.135 Necrosis factor: Present/Absent P=0.967 Vascular emboli: Present/Absent P=0.6968 Chi Square test Inflammatory infiltrate: Present/Absent P=0.015 Multifocal tumor: Yes/No P=0.4474 Immunohistochemical profile: Luminal B-Her2 P=0.0106 negative/A/Triple negative N-stage: N0/N1 P=0.5759 Clujul Medical Vol. 91, No. 2, 2018: 197-202 199 Surgery Discussion mm cut-off between intraoperative ultrasonography and The evaluation of the final histopathological result excised specimen mammography, a higher accuracy of the in BCS occupies a particularly important place in the first method in margin status assessment (90%) is shown current literature, which is why we considered it necessary with a re-excision rate in the secondary operating time of to compare the results obtained in the present study with 9%. Devolli D et al. in a study of 546 patients showed the other clinical trials. superiority of ultrasonography with predilection in young The MAIN OBJECTIVE was the correlation between and dense breasts. Another study by Lehman CD and the final interpretation of the histopathological exam with collaborators on a group of 954 patients supports the results intraoperative ultrasound, respectively mammogram of of our study, in their case the sensitivity in ultrasonography the excised specimen. In recent years, numerous studies being 95.7% compared to 60.9% in mammography [24,32]. have evaluated various techniques of obtaining negative The SECOND OBJECTIVE of the study was the histopathological margins, and the two methods currently evaluation of the various parameters in relation to the constitute, according to the literature, techniques with a positive margin status. fairly high accuracy in the assessment of margin status. Thus, correlating the age groups with the final Intraoperative ultrasonography histopathological results in a statistically significant For a 2 mm cut-off , our study results showed association (p<0.01) due to the dense breast tissue a sensitivity of 90.91%, a specificity of 67.21% and a p consistency and negative ER for the under 40-year-old value=0.018. The re-excision rate in a second, postoperative group. Similar results have been reported in other studies time was 9% (1 case) while the primary reexcision rate for such as those published by Devolli D, Scaranelo AM, at least one excised specimen margin was 30% (25 cases). Jobsen JJ and Vrieling C [23,24,33,34]. Various studies are available in the literature to The use of preoperative chemotherapy is also evaluate intraoperative ultrasonography, whose values are statistically associated with the histopathological outcome close to those obtained in our study. Of these, it is worth (p=0.0302) because the reduction in tumor volume following mentioning the study by Scaranelo A.M. in which the adjuvant therapy is not always concentric, making it more sensitivity of the method was 100% and the specificity 59%, difficult to obtain free tumor margins [29,35]. the study by Eichler C. in which resection was achieved in Regarding the histological type, the values obtained 96.4% (81) patients in the ultrasound group compared to from the study showed a statistically significant association 82.5% (137) in the control group. Another study conduced between the presence of intraductal carcinoma or combined by Karanlik H obtained adequate resection on 94 % of with intralobular carcinoma and marginal positive status patients in the US-guided surgery group and on 83 % of (p=0.04069) due to the type of extension that characterizes patients in the palpation guided group (p=0.03). However, this tissue. This is consistent with similar studies which Olsha O. et al in a study on 45 patients conclude that showed the impact of the aforementioned parameter on the intraoperative ultrasonography tends to overestimate the marginal status [15,23,29,36]. real margin width, reporting the sensitivity and specificity The presence of inflammatory infiltrate in the tumor equal with 25% and 95%, respectively [22,23,30,31]. bed correlates with the marginal positive status (p=0.015) Specimen mammography because ultrasounds are pulsed rather than transmitted For a 2 mm cut-off the results of our study showed continuously. This causes a less precise delimitation a sensitivity of 45.45%, a specificity of 85.25% and p value between malignant and healthy tissue. of 0.18. The re- excision rate in a second operating time A substantial part of the literature links some subtypes would have been 6% (5 cases) while the primary reexcision of the immunohistochemical profile with the marginal rate for at least one margin of the excised specimen was positive status and a high rate of recurrence [14,29,35]. In 15% (11 cases). the present paper, the triple negative profile statistically Various studies are available in the literature to changes the histopathological end result (p=0.0106) due to evaluate the mammography of the excised specimen, the aggressive character and the presence of the intraductal whose values are close to those obtained in the present component. study. Among them we mention the study of Bathla L In terms of tumor size, tumor degree, presence of et al. in which the sensitivity of the method was 20.6% microcalcifications, necrosis factor, vascular embolisms, and the specificity 94.6%, the study by Hisada T et al. in multifocal tumors and tumor infiltrating lymph nodes, a which the sensitivity of the method was 58.5% and the statistically significant association with the marginal positive specificity of 91.8%, the study by McCormick TJ et al. status was not found, although some of these parameters in which sensitivity was 54.55%, and the specificity was influence the histopathological outcome [3,29,33,35,36]. 87.80%[25,26,27] The explanation would be that, in terms of tumor size, Intraoperative ultrasonography versus specimen 67.5% of patients have tumors below 2 mm; 1.2% have mammography grade 3 and the rest grade 1 and 2; Although 43.3% of the Further, comparing the results obtained for a 2 patients had microcalcifications, only 13.8% had marginal Clujul Medical Vol. 91, No. 2, 2018: 197-202 200 Original Research N. Twenty-five-year follow-up of a randomized trial comparing positive status. According to the results, a small number radical mastectomy, total mastectomy, and total mastectomy of patients had necrosis and vascular emboli at tumor bed: followed by irradiation. N Engl J Med. 2002;347(8):567-575. 21.6% and 27.7%,respectively. Considering the presence of 8. Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, multifocal tumors (10.84%) and tumor infiltrating lymph Luini A, et al. Twenty-year follow-up of a randomized study nodes (27.7%), there was also no statistical correlation with comparing breast-conserving surgery with radical mastectomy for the histopathological outcome. early breast cancer. N Engl J Med. 2002;347(16):1227-1232. Clearly, our study had some limitations. Among 9. Houssami N, Macaskill P, Marinovich ML, Dixon JM, Irwig these, the small number of cases included in the study group L, Brennan ME, et al. Meta-analysis of the impact of surgical compared to other studies addressing the same subject, as margins on local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy. Eur J Cancer. well as the impossibility to perform mammography of the 2010;46:3219-3232. excised intraoperative specimen, that would probably have 10. Smitt MC, Nowels K, Carlson RW, Jeffrey SS. Predictors of brought to light certain changes in the tumor bed, which reexcision findings and recurrence after breast conservation. Int J ultrasonography is not capable of assessing with the same Radiat Oncol Biol Phys. 2003;57:979–985. accuracy. 11. Sarrazin D, Arriagada R, Contesso G, Fontaine F, Spielmann M, et al. Ten-year results of a randomized trial comparing a Conclusions conservative treatment to mastectomy in early breast cancer. In the study of 83 patients, diagnosed with early- Elsevier Science Publishers B.V. 1989;14:177-184. 12. Smitt MC, Nowels KW, Zdeblick MJ, Jeffrey S, Carlson RW, stage breast cancer (pT1-3a pN0-1 M0), subjected to Stockdale FE, et al. The importance of the lumpectomy surgical surgical treatment at the Department of Surgery 1, Mureş margin status in long-term results of breast conservation. Cancer. County Clinical Hospital from January 2014 to December 1995;76(2):259-267. 2016, the following were demonstrated: 13. START Trialists’ Group, Bentzen SM, Agrawal RK, Aird EG, - Intraoperative ultrasonography is superior to Barrett JM, Barrett-Lee PJ et al. The UK Standardisation of Breast mammography of the excised specimen for a 2 mm cut-off, Radiotherapy (START) Trial A of radiotherapy hypofractionation being a safe, fast, cheap, radiation-free method with a fairly for treatment of early breast cancer: a randomised trial. Lancet high availability in any health care center. Oncol. 2008;9:331–341. - Concerning the cut-off that we should consider in 14. Moran MS, Schnitt SJ, Giuliano AE, Harris JR, Khan SA, Horton J, et al. Society of Surgical Oncology-American Society ultrasonography, our study proves the 2 mm cut-off is more for Radiation Oncology consensus guideline on margins for appropriate considering that we are talking about a surgical breast-conserving surgery with whole-breast irradiation in stage technique that attempts to preserve the breast. I and II invasive breast cancer. Int J Radiat Oncol Biol Phys. - Excision specimen mammography is an adjuvant 2014;88(3):553–564. method of ultrasonography due to a higher precision in cases 15. Pleijhuis RG, Graafland M, de Vries J, Bart J, de Jong JS, where parenchymal microcalcifications and distortions are van Dam GM. Obtaining adequate surgical margins in breast- present. conserving therapy for patients with early-stage breast cancer: - According to our study, particular attention current modalities and future directions. 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Obtaining adequate surgical margin status in breast-conservation therapy: intraoperative ultrasound-guided resection versus specimen mammography

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Pubmed Central
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1222-2119
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2066-8872
DOI
10.15386/cjmed-891
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Abstract

Background and aim. The purpose of breast-conserving surgery (BCS) for women with cancer is to perform an oncological radical procedure with disease-free margins at the final histological assessment and with the best aesthetic result possible. Intraoperative resected specimen ultrasound and intraoperative resected specimen mammography may reduce the rates of positive margins and reexcision among patients undergoing conserving therapy. Our objective is to compare the two methods with the histopathological results for a preset cut off and asses which parameters can influence the positive margin status. Method. A prospective study was performed on 83 patients who underwent breast conservation surgery for early breast cancer (pT1-3a pN0-1 M0) between 2014 and 2016. After excision the specimen was oriented in the operating room by the surgeon. Metallic clips and threads were placed on margins: one clip and the long thread at 12 o’clock, two clips and the short threads at 9 o’clock. The next step was intraoperative ultrasound assessment of the specimen. For the margins under 2 mm we performed selective margin shaving, followed by mammography to identify and document the lesion and finally histopathological examination of the specimen with reporting the gross and microscopic margins. The positive margins required re-excision or boost of radiation at the posterior or anterior margins, depending on the case. Results. We set a cut-off at 2 mm. The sensitivity and specificity of the intraoperative margin assessment via the ultrasound method were 90.91% (95% CI 70.84-98.88%) and 67.21% (95% CI 54-78.69%) respectively. The sensitivity and specificity of the intraoperative margin assessment via the mammographic procedure were 45.45% (95% CI 24.39-67.79%) and 85.25% (95% CI 73.83-93.02%) respectively. There was positive correlation between the histopathological and intraoperative ultrasound exam (p=0.018) and negative correlation between the histopathological exam and the post-operative mammographic exam (p=0.68). We found a positive correlation between the positive margin status and age (<40), preoperative chemotherapy, intraductal carcinoma, inflammatory process around the tumor, and the immunohistochemical triple negative profile. Conclusions. According to our results, the intraoperative ultrasound of the breast specimen for a cutt-off at 2 mm can decrease the rates of margin positivity compared to the mammographic procedure and has the potential to diminish the number of subsequent undesired re-excisions. Keywords: breast-conserving surgery, intraoperative ultrasound, specimen mammography Manuscript received: 15.09.2017 Received in revised form: 01.12.2017 Accepted: 24.01.2018 Address for correspondence: sylvinho_46@yahoo.com Clujul Medical Vol. 91, No. 2, 2018: 197-202 197 Surgery Background and aims histopathological examination in order to obtain a negative Surgery continues to be the main pillar of breast margin status for a preset cut-off. The secondary objective cancer therapy nowadays. With the development and is to determine the parameters that can influence margin widespread of breast cancer diagnostic techniques, the status. addition of adjuvant therapy, the expansion of knowledge in the field of cancer biology have led in recent decades Methods to the narrowing of the operative act and the emergence Eligibility. An observational prospective study of a new concept: conservative surgery. As an alternative was performed on 83 patients who underwent breast to mastectomy, conservative surgery pursues two goals: conservation surgery (BCS) for early breast cancer (pT1-3a effective local oncology (radicality) and achieving the pN0-1 M0) between 2014 and 2016 in Tîrgu Mureş County best aesthetic result possible, with the main focus being Hospital, Department of General Surgery. The study was on the principle of radicalism [1,2]. Surgical treatment approved by the Ethics Committees of the Tîrgu Mureş for early stage breast cancer hasn’t always been breast County Hospital and of the University of Medicine and conservative. In 1894 William Halsted revolutionized his Pharmacy of Tîrgu Mureş. Pregnant women, patients with time with the radical mastectomy. Half a century later, in benign pathology at final histopathological assessment, 1948 Patey and Madden refined the procedure, introducing patients unable to receive anesthesia or those refusing the modified radical mastectomy [3,4,5]. Medicine evolved surgical treatment, were excluded. and paradigms shifted, making breast conservation therapy Clinical Protocol. During the operation, after the desired technique after the 1991 National Institute of excision, the specimen was oriented in the operating room Health Consensus on breast cancer, determined by the by the surgeon. Metallic clips and threads were placed on Veronessi and Fisher studies, a few years earlier [6,7,8]. the margins: one clip and the long thread at 12 o’clock, two The goal for patients with early breast cancer is to clips and the short threads at 9 o’clock. The next step was obtain negative margins at the final histological assessment intraoperative ultrasound assessment of the specimen, using [9,10]. Among the first trials to deal with this matter were Philips ClearVue 650 with the frequency linear transducer the ones published by Gustave Roussy Institute (1988), set at 12 MHz. The procedure was performed directly on Stanford University Medical Center (1972-1992) and the specimen after resection, without prior immersion START trial (1992-2002) [11,12,13]. The 2014 guidelines of the surgical piece in saline solution. Selective margin endorsed by SSO-ASTRO Consensus, advocate no ink on shavings were carried out for close margins (<2 mm) at tumor as the new margin requirement. This approach to the discretion of the surgeon and the new margins of the breast cancer has gained rapid followers around the world, additional resections were oriented by sutures. Afterwards being today a commonly recognized treatment method [14]. intraoperative resected specimen mammography was The current intra-operative trend is the simultaneous performed, and six radial distances from all margins use of diagnostic and therapeutic procedures, resulting in the (superior, inferior, lateral, medial, anterior and posterior) so-called ”theranostic” procedure in which intraoperative were recorded to identify and document the targeted lesion. ultrasonography plays an important role in assessing Finally, the specimens were evaluated by board certified marginal status and having the ability to differentiate pathologists who painted the six surfaces and reported normal tissue from benign or malignant changes [15,16,17]. the gross and microscopic margins. The new resection In 1988, Schwartz published a study using ultrasound as margins of the additional intraoperative resections were an alternative technique for detecting non-palpable breast also inked. The tissue specimen and additional resections tumors [18,19]. Since then, other studies have sought to were serially sectioned at 3- to 3-mm intervals and stained confirm the feasibility and safety of the impalpable and by hematoxylin and eosin. Reoperation was recommended palpable breast tumor method [20-24]. Another approach for any margin <2 mm at the pathology assessment. designed to achieve negative margins is mammography of Statistical analysis. The analysis was made on the the specimen. The accuracy of the method is determined by number of patients on whom the methods demonstrated its ability to provide information on the presence or absence evidence of tumor cells at least one resection margin or of microcalcifications, but also on parenchymal distortions very close to a margin (<2 mm). Subsequently the data [25,26,27]. Among the limitations of this technique are the was processed using Microsoft Office Excel 2010 tables. “pancake” phenomenon and the existence of an invasive Calculation of sensitivity and specificity were performed lobular carcinoma surrounded by dense tissue. The latter using MedCalc 17.4.4. The results were further compiled requires, according to the 2005 Consensus Statement using the GraphPad Prism 6 program. The correlation of issued by the American Society of Breast Surgeons, the use the different parameters required the application of tests of MRI over mammography [28,29]. such as: test T student for non-paired data, Fisher test, Chi The main aim of the study is the evaluation of square test. P values < 0.05 were considered statistically intraoperative ultrasonography and mammography of significant. the specimen excised according to the final result of the Clujul Medical Vol. 91, No. 2, 2018: 197-202 198 Original Research Results 70.84-98.88%) and specificity of 67.21 % (95% CI 54- The study group included 83 patients aged between 78.69%) in the evaluation of surgical pathology margins 33-89 years with the median age of 57.3. They were (Figure 1, Table I). Regarding the specimen mammography divided into 2 age subgroups: <40 years (n=10), ≥40 years margins with 2 mm cut-off, the sensibility and specificity (n=73). 74 (89%) patients had a tumor-free margin. Of were 45.45% (95% CI 24.39-67.79%) respectively 85.25% note, a tumor-free margin was defined as ‘no tumor on ink’. (95% CI 73.83-93.02%) (Figure 2, Table II). Specimen ultrasound (hypoechoic targeted mass found <2 The correlation between different parameters and mm from the edge) had a sensitivity of 90.91 % ( 95% CI the marginal status is exemplified in Table III. Figure 1. ROC Curve regarding the comparison of specimen Figure 2. ROC Curve regarding the comparison of specimen ultrasound margins with surgical pathology 2 mm cut-off. mammography margins with surgical pathology 2 mm cut off. Table I. Comparison of specimen ultrasound margins with surgical pathology (cut off=2 mm). Specimen ultrasound Surgical pathology positive Margins report negative Total Positive (<2 mm) 8 (true positive) 25 (false positive) 33 Negative (>2 mm) 1 (false negative) 49 (true negative) 50 Total 9 74 83 Table II. Comparison of specimen mammography margins with surgical pathology (cut off=2 mm). Specimen mammography Surgical pathology positive Margins report negative Total Positive (<2 mm) 4 (true positive) 11 (false positive) 15 Negative (>2 mm) 5 (false negative) 63 (true negative) 68 Total 9 74 83 Table III. The correlation between different parameters and the surgical margin status. Variable Applied Test P value Age: <40 or ≥40 P<0.01 Unpaired T test Tumor size <20 mm or >20 mm P=0.965 Preoperative chemotherapy: Yes/ No P=0.0302 Fisher test Histologic type: Ductal/lobular/others P=0.0406 Grade: 1/2/3 P=0.144 Microcalcifications: Present/Absent P=0.135 Necrosis factor: Present/Absent P=0.967 Vascular emboli: Present/Absent P=0.6968 Chi Square test Inflammatory infiltrate: Present/Absent P=0.015 Multifocal tumor: Yes/No P=0.4474 Immunohistochemical profile: Luminal B-Her2 P=0.0106 negative/A/Triple negative N-stage: N0/N1 P=0.5759 Clujul Medical Vol. 91, No. 2, 2018: 197-202 199 Surgery Discussion mm cut-off between intraoperative ultrasonography and The evaluation of the final histopathological result excised specimen mammography, a higher accuracy of the in BCS occupies a particularly important place in the first method in margin status assessment (90%) is shown current literature, which is why we considered it necessary with a re-excision rate in the secondary operating time of to compare the results obtained in the present study with 9%. Devolli D et al. in a study of 546 patients showed the other clinical trials. superiority of ultrasonography with predilection in young The MAIN OBJECTIVE was the correlation between and dense breasts. Another study by Lehman CD and the final interpretation of the histopathological exam with collaborators on a group of 954 patients supports the results intraoperative ultrasound, respectively mammogram of of our study, in their case the sensitivity in ultrasonography the excised specimen. In recent years, numerous studies being 95.7% compared to 60.9% in mammography [24,32]. have evaluated various techniques of obtaining negative The SECOND OBJECTIVE of the study was the histopathological margins, and the two methods currently evaluation of the various parameters in relation to the constitute, according to the literature, techniques with a positive margin status. fairly high accuracy in the assessment of margin status. Thus, correlating the age groups with the final Intraoperative ultrasonography histopathological results in a statistically significant For a 2 mm cut-off , our study results showed association (p<0.01) due to the dense breast tissue a sensitivity of 90.91%, a specificity of 67.21% and a p consistency and negative ER for the under 40-year-old value=0.018. The re-excision rate in a second, postoperative group. Similar results have been reported in other studies time was 9% (1 case) while the primary reexcision rate for such as those published by Devolli D, Scaranelo AM, at least one excised specimen margin was 30% (25 cases). Jobsen JJ and Vrieling C [23,24,33,34]. Various studies are available in the literature to The use of preoperative chemotherapy is also evaluate intraoperative ultrasonography, whose values are statistically associated with the histopathological outcome close to those obtained in our study. Of these, it is worth (p=0.0302) because the reduction in tumor volume following mentioning the study by Scaranelo A.M. in which the adjuvant therapy is not always concentric, making it more sensitivity of the method was 100% and the specificity 59%, difficult to obtain free tumor margins [29,35]. the study by Eichler C. in which resection was achieved in Regarding the histological type, the values obtained 96.4% (81) patients in the ultrasound group compared to from the study showed a statistically significant association 82.5% (137) in the control group. Another study conduced between the presence of intraductal carcinoma or combined by Karanlik H obtained adequate resection on 94 % of with intralobular carcinoma and marginal positive status patients in the US-guided surgery group and on 83 % of (p=0.04069) due to the type of extension that characterizes patients in the palpation guided group (p=0.03). However, this tissue. This is consistent with similar studies which Olsha O. et al in a study on 45 patients conclude that showed the impact of the aforementioned parameter on the intraoperative ultrasonography tends to overestimate the marginal status [15,23,29,36]. real margin width, reporting the sensitivity and specificity The presence of inflammatory infiltrate in the tumor equal with 25% and 95%, respectively [22,23,30,31]. bed correlates with the marginal positive status (p=0.015) Specimen mammography because ultrasounds are pulsed rather than transmitted For a 2 mm cut-off the results of our study showed continuously. This causes a less precise delimitation a sensitivity of 45.45%, a specificity of 85.25% and p value between malignant and healthy tissue. of 0.18. The re- excision rate in a second operating time A substantial part of the literature links some subtypes would have been 6% (5 cases) while the primary reexcision of the immunohistochemical profile with the marginal rate for at least one margin of the excised specimen was positive status and a high rate of recurrence [14,29,35]. In 15% (11 cases). the present paper, the triple negative profile statistically Various studies are available in the literature to changes the histopathological end result (p=0.0106) due to evaluate the mammography of the excised specimen, the aggressive character and the presence of the intraductal whose values are close to those obtained in the present component. study. Among them we mention the study of Bathla L In terms of tumor size, tumor degree, presence of et al. in which the sensitivity of the method was 20.6% microcalcifications, necrosis factor, vascular embolisms, and the specificity 94.6%, the study by Hisada T et al. in multifocal tumors and tumor infiltrating lymph nodes, a which the sensitivity of the method was 58.5% and the statistically significant association with the marginal positive specificity of 91.8%, the study by McCormick TJ et al. status was not found, although some of these parameters in which sensitivity was 54.55%, and the specificity was influence the histopathological outcome [3,29,33,35,36]. 87.80%[25,26,27] The explanation would be that, in terms of tumor size, Intraoperative ultrasonography versus specimen 67.5% of patients have tumors below 2 mm; 1.2% have mammography grade 3 and the rest grade 1 and 2; Although 43.3% of the Further, comparing the results obtained for a 2 patients had microcalcifications, only 13.8% had marginal Clujul Medical Vol. 91, No. 2, 2018: 197-202 200 Original Research N. Twenty-five-year follow-up of a randomized trial comparing positive status. According to the results, a small number radical mastectomy, total mastectomy, and total mastectomy of patients had necrosis and vascular emboli at tumor bed: followed by irradiation. N Engl J Med. 2002;347(8):567-575. 21.6% and 27.7%,respectively. Considering the presence of 8. Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, multifocal tumors (10.84%) and tumor infiltrating lymph Luini A, et al. Twenty-year follow-up of a randomized study nodes (27.7%), there was also no statistical correlation with comparing breast-conserving surgery with radical mastectomy for the histopathological outcome. early breast cancer. N Engl J Med. 2002;347(16):1227-1232. Clearly, our study had some limitations. Among 9. Houssami N, Macaskill P, Marinovich ML, Dixon JM, Irwig these, the small number of cases included in the study group L, Brennan ME, et al. Meta-analysis of the impact of surgical compared to other studies addressing the same subject, as margins on local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy. Eur J Cancer. well as the impossibility to perform mammography of the 2010;46:3219-3232. excised intraoperative specimen, that would probably have 10. Smitt MC, Nowels K, Carlson RW, Jeffrey SS. Predictors of brought to light certain changes in the tumor bed, which reexcision findings and recurrence after breast conservation. Int J ultrasonography is not capable of assessing with the same Radiat Oncol Biol Phys. 2003;57:979–985. accuracy. 11. Sarrazin D, Arriagada R, Contesso G, Fontaine F, Spielmann M, et al. Ten-year results of a randomized trial comparing a Conclusions conservative treatment to mastectomy in early breast cancer. In the study of 83 patients, diagnosed with early- Elsevier Science Publishers B.V. 1989;14:177-184. 12. 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Published: Apr 25, 2018

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