Impact on the recall rate of digital breast tomosynthesis as an adjunct to digital mammography in the screening setting. A double reading experience and review of the literature 數位乳腺斷層合成作為數位乳房攝影輔助檢查對召回率的影響。在篩檢環境中的雙重閱讀經驗及文獻回顧
Luca A. Carbonaro ^(a){ }^{\mathrm{a}}, Giovanni Di Leo ^(a){ }^{\mathrm{a}}, Paola Clauser ^(b,c,**){ }^{\mathrm{b}, \mathrm{c}, *}, Rubina M. Trimboli ^(a){ }^{\mathrm{a}}, Nicola Verardi ^("a "){ }^{\text {a }}, Maria P. Fedeli ^("d "){ }^{\text {d }}, Rossano Girometti ^("b "){ }^{\text {b }}, Alfredo Tafà ^(e){ }^{e}, Paola Bruscoli ^(e){ }^{e}, Gianni Saguatti ^("e "){ }^{\text {e }}, Massimo Bazzocchi ^("b "){ }^{\text {b }}, Francesco Sardanelli ^("a,f "){ }^{\text {a,f }} 盧卡·A·卡爾博納羅 ^(a){ }^{\mathrm{a}} , 喬瓦尼·迪·萊奧 ^(a){ }^{\mathrm{a}} , 保拉·克勞瑟 ^(b,c,**){ }^{\mathrm{b}, \mathrm{c}, *} , 露比娜·M·特林博利 ^(a){ }^{\mathrm{a}} , 尼科拉·維拉爾迪 ^("a "){ }^{\text {a }} , 瑪麗亞·P·費德利 ^("d "){ }^{\text {d }} , 羅薩諾·吉羅梅蒂 ^("b "){ }^{\text {b }} , 阿爾弗雷多·塔法 ^(e){ }^{e} , 保拉·布魯斯科利 ^(e){ }^{e} , 吉安尼·薩古阿提 ^("e "){ }^{\text {e }} , 馬西莫·巴佐基 ^("b "){ }^{\text {b }} , 法蘭西斯科·薩爾達內利 ^("a,f "){ }^{\text {a,f }}^(a){ }^{a} Radiology Unit, Research Hospital Policlinico San Donato, San Donato Milanese, Milan, Italy ^(a){ }^{a} 放射科，聖多納托研究醫院，聖多納托米蘭，米蘭，意大利^(b){ }^{\mathrm{b}} Institute of Radiology, Department of Medical and Biological Sciences, University of Udine, Udine, Italy ^(b){ }^{\mathrm{b}} 烏迪內大學醫學與生物科學系放射學研究所，意大利烏迪內^("c "){ }^{\text {c }} Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Austria 維也納醫科大學，奧地利，生物醫學影像與影像引導治療系，分子與性別影像部門^("d "){ }^{\text {d }} Scuola di Specializzazione in Radiodiagnostica, Università degli Studi di Milano, Milan, Italy 米蘭大學放射診斷專科學校，意大利米蘭^("e Unità Operativa di Senologia, Ospedale Maggiore, AUSL Bologna, Bologna, Italy "){ }^{\text {e Unità Operativa di Senologia, Ospedale Maggiore, AUSL Bologna, Bologna, Italy }}^(f){ }^{\mathrm{f}} Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy ^(f){ }^{\mathrm{f}} 米蘭大學生物醫學科學系，意大利米蘭
A R TICLE INFO 文章資訊
Article history: 文章歷史：
Received 20 September 2015 收到日期：2015 年 9 月 20 日
Received in revised form 12 January 2016 修訂版收到於 2016 年 1 月 12 日
Accepted 13 January 2016 接受日期：2016 年 1 月 13 日
Keywords: 關鍵詞：
Breast cancer 乳腺癌
Digital breast tomosynthesis (DBT) 數位乳房斷層合成 (DBT)
Digital mammography (DM) 數位乳房攝影 (DM)
Recall rate 回收率
Screening 篩檢
population based 基於人口的
Abstract 摘要
Objectives: To estimate the impact on recall rate (RR) of digital breast tomosynthesis (DBT) associated with digital mammography (DM + DBT), compared to DM alone, evaluate the impact of double reading (DR) and review the literature. Methods: Ethics committees approved this multicenter study. Patients gave informed consent. Women recalled from population-based screening reading were included. Reference standard was histology and/or >= 1\geq 1 year follow up. Negative multiple assessment was considered for patients lost at follow up. Two blinded readers (R1, R2) evaluated first DM and subsequently DM + DBT. RR, sensitivity, specificity, accuracy, positive and negative predictive values (PPV, NPV), were calculated for R1, R2, and DR. Cohen kappa\kappa and chi^(2)\chi^{2} were used for R1-R2 agreement and RR related to breast density. Results: We included 280 cases ( 41 malignancies, 66 benign lesions, and 173 negative examinations). The RR reduction was 43%43 \% (R1), 58%58 \% (R2), 43% (DR). Sensitivity, specificity, accuracy, PPV and NPV were: 93%93 \%, 67%,71%,33%,98%67 \%, 71 \%, 33 \%, 98 \% for R1; 88%,73%,75%,36%,97%88 \%, 73 \%, 75 \%, 36 \%, 97 \% for R2; 98%,55%,61%,27%,99%98 \%, 55 \%, 61 \%, 27 \%, 99 \% for DR. The agreement was higher for DM+DBT(kappa=0.459\mathrm{DM}+\mathrm{DBT}(\kappa=0.459 versus kappa=0.234\kappa=0.234 ). Reduction in RR was independent from breast density ( p=0.992p=0.992 ). Conclusion: DBT was confirmed to reduce RR, as shown by 13 of 15 previous studies (reported reduction 6-82%6-82 \%, median 31%31 \% ). This reduction is confirmed when using DR. DBT allows an increased inter-reader agreement. 目標：估計數位乳房斷層攝影（DBT）與數位乳房攝影（DM + DBT）相關的召回率（RR）影響，與僅使用 DM 相比，評估雙重閱讀（DR）的影響並回顧文獻。方法：倫理委員會批准了這項多中心研究。患者提供知情同意。從基於人群的篩查中召回的女性被納入研究。參考標準為組織學和/或 >= 1\geq 1 年隨訪。對於在隨訪中失聯的患者，考慮了負面多重評估。兩位盲讀者（R1，R2）首先評估 DM，隨後評估 DM + DBT。計算 R1、R2 和 DR 的 RR、敏感性、特異性、準確性、陽性和陰性預測值（PPV，NPV）。使用 Cohen kappa\kappa 和 chi^(2)\chi^{2} 來評估 R1-R2 的一致性及與乳腺密度相關的 RR。結果：我們納入了 280 例（41 例惡性腫瘤，66 例良性病變，173 例陰性檢查）。RR 減少為 43%43 \% （R1）， 58%58 \% （R2），43%（DR）。敏感性、特異性、準確性、PPV 和 NPV 為： 93%93 \% ， 67%,71%,33%,98%67 \%, 71 \%, 33 \%, 98 \% （R1）； 88%,73%,75%,36%,97%88 \%, 73 \%, 75 \%, 36 \%, 97 \% （R2）； 98%,55%,61%,27%,99%98 \%, 55 \%, 61 \%, 27 \%, 99 \% （DR）。對於 DM+DBT(kappa=0.459\mathrm{DM}+\mathrm{DBT}(\kappa=0.459 與 kappa=0.234\kappa=0.234 的協議更高。RR 的減少與乳腺密度無關（ p=0.992p=0.992 ）。 結論：DBT 被確認能降低 RR，這在 15 項先前研究中有 13 項顯示（報告的減少 6-82%6-82 \% ，中位數 31%31 \% ）。使用 DR 時，這一減少得到了確認。DBT 允許提高讀者間的一致性。
Clinical trials have shown that screening mammography is able to reduce mortality from breast cancer [1]. Even though, there is still intense discussion and criticism regarding screening programs [2]. Being a two-dimensional imaging method, digital mammography (DM) has several limitations: small lesions can be hidden by dense 臨床試驗顯示，篩檢乳房攝影能夠降低乳腺癌的死亡率[1]。儘管如此，對於篩檢計劃仍然存在激烈的討論和批評[2]。作為一種二維影像方法，數位乳房攝影（DM）有幾個限制：小病變可能會被致密組織隱藏。
breast parenchyma and thus cancers can be missed, especially in women with dense breasts [3]. On the other hand, the superimposition of normal breast glandular tissue can create false images, leading to a high percentage of unnecessary recalls. Furthermore, with the introduction of screening mammography, the diagnosis of lesions with unknown or low clinical significance has increased, raising the issues of overdiagnosis and overtreatment [4]. 乳腺實質，因此癌症可能會被漏診，特別是在乳腺密度較高的女性中 [3]。另一方面，正常乳腺腺體組織的重疊可能會產生假影像，導致不必要的回診比例偏高。此外，隨著篩檢乳房攝影的引入，對於臨床意義不明或低的病變的診斷增加，提出了過度診斷和過度治療的問題 [4]。
Recalling patients for further examinations (additional mammographic views, ultrasound, magnetic resonance imaging, or even biopsy) is cause of anxiety for the women and determines significant additional costs for screening programs [5]. According to European and U.S. guidelines, recall rates should be kept beneath 7%7 \% and 12%12 \%, respectively [6,7]; these different thresholds are due to 召回患者進行進一步檢查（額外的乳房攝影檢查、超聲波、磁共振成像，甚至活檢）會引起女性的焦慮，並為篩檢計劃帶來顯著的額外成本 [5]。根據歐洲和美國的指導方針，召回率應分別保持在 7%7 \% 和 12%12 \% 之下 [6,7]；這些不同的閾值是由於
the variability in clinical practice, with higher recall rates in the U.S., as compared to European countries [8]. The site where mammography is interpreted has also been found to influence the number of women recalled [9]. These differences are not associated with a comparable variability in detection rate, which does not improve with higher recalls [10]. 臨床實踐中的變異性，在美國的召回率高於歐洲國家[8]。進行乳房攝影解讀的地點也被發現會影響被召回的女性數量[9]。這些差異與檢出率的變異性無關，且在召回率提高的情況下，檢出率並未改善[10]。
Digital breast tomosynthesis (DBT), used in association with DM, is able to detect a higher number of cancers, compared to DM alone. In particular, initial result of trials, both in Europe and in the U.S., showed that DBT in the screening setting is able to enhance the number of invasive malignant lesions diagnosed. At the same time, thanks to its capability to obtain various images of the same breast and reduce the effect of tissue superimposition, studies showed that DBT is able to reduce the number of women recalled because of unspecific findings and false positives mammographic images [11]. 數位乳房斷層合成（DBT）與乳房攝影（DM）結合使用，能夠檢測到比單獨使用 DM 更多的癌症。特別是，歐洲和美國的初步試驗結果顯示，DBT 在篩檢環境中能夠提高診斷到的侵襲性惡性病變的數量。與此同時，得益於其獲取同一乳房的多種影像並減少組織重疊效應的能力，研究顯示 DBT 能夠減少因非特異性發現和假陽性乳房攝影影像而被召回的女性數量[11]。
In this study we aimed at evaluating the effect on recall rate of two-view DBT in association with DM, as compared to DM alone. Furthermore, we assessed inter-reader agreement and whether breast density influenced the effect of DBT on recall rates. Finally, we performed a review of the literature published on this topic. 在本研究中，我們旨在評估兩視圖數位乳腺攝影（DBT）與乳腺密度（DM）聯合使用對回診率的影響，與僅使用乳腺密度相比。此外，我們評估了讀者間的一致性以及乳腺密度是否影響 DBT 對回診率的效果。最後，我們對該主題的文獻進行了回顧。
2. Materials and methods 2. 材料與方法
2.1. Study population and screening reading protocol 2.1. 研究人群及篩檢閱讀協議
This multicenter prospective study obtained the ethics committee approval at all three centers involved, and the patients included signed a written informed consent. Between January 2012 and December 2013 all women recalled from the screening program and afferent to the involved institutions for diagnostic work-up could be enrolled in this study. In two of the three regions involved, screening mammography is offered every second year to women between 50 and 69 years of age. In the third region, screening mammography is offered annually from 45 to 49 years and every second year from 50 to 75 years. 這項多中心前瞻性研究已獲得所有三個參與中心的倫理委員會批准，參與的患者簽署了書面知情同意書。在 2012 年 1 月至 2013 年 12 月期間，所有從篩檢計劃中召回並轉介至參與機構進行診斷工作的女性均可參加本研究。在三個參與地區中的兩個地區，對於 50 至 69 歲的女性，每兩年提供一次篩檢乳房攝影。在第三個地區，對於 45 至 49 歲的女性，每年提供一次篩檢乳房攝影，對於 50 至 75 歲的女性則每兩年提供一次。
In all three centers involved, the readings for population based screening program were performed by two independent readers. When both readers identified a finding deserving further characterization, the woman was recalled. When the opinion of the two readers was discordant, the decision to recall or not the woman was taken either with a consensus reading or by showing the examination to a third, blinded, radiologist. The screening readers of the three centers were not involved in the readings of the current study. 在所有三個參與的中心，基於人群的篩檢計劃的讀數由兩位獨立的讀者進行。當兩位讀者都識別出需要進一步特徵化的發現時，該女性會被召回。當兩位讀者的意見不一致時，是否召回該女性的決定要麼通過共識讀取做出，要麼通過將檢查結果展示給第三位盲法放射科醫生來決定。三個中心的篩檢讀者未參與本研究的讀數。
Exclusion criteria were: lack of written informed consent, mammography performed in symptomatic patients, breast implant in the breast with the suspicious finding(s), and pregnancy. 排除標準包括：缺乏書面知情同意、在有症狀的患者中進行乳房攝影、懷疑發現的乳房中有乳房植入物，以及懷孕。
The final study population consisted of women recalled from the regional screening programs that agreed in participating in the study and had no exclusion criteria. 最終研究人群由從區域篩檢計劃中召回的女性組成，她們同意參加研究且沒有排除標準。
2.2. DBT acquisition protocol 2.2. DBT 獲取協議
Patients recalled from the screening program who agreed in participating in the study underwent, after bilateral DM, DBT of the breast harboring the finding that prompted the recall. Each exam was performed on both standard views (cranio-caudal and mediolateral oblique). The same mammographic unit (Giotto Tomo, Internazionale Medico-Scientifica, Bologna, Italy) was used at each of the three centers, equipped with an amorphous-selenium digital detector (ANRAD), with a sensitive area of 24 xx30cm^(2)24 \times 30 \mathrm{~cm}^{2} and a squared pixel pitch of 0.085 mm , resulting in an image size of 2816 xx35842816 \times 3584 pixels. Images of the included cases were anonymized and stored in a dedicated workstation. 從篩檢計畫中召回的患者同意參加研究後，經過雙側數位乳腺攝影（DM），進行了針對引發召回的發現的乳腺數位斷層攝影（DBT）。每次檢查均在標準視圖（頭尾方向和內外斜視）下進行。三個中心均使用相同的乳腺攝影設備（Giotto Tomo，Internazionale Medico-Scientifica，意大利博洛尼亞），配備有非晶硒數位探測器（ANRAD），敏感區域為 24 xx30cm^(2)24 \times 30 \mathrm{~cm}^{2} ，方形像素間距為 0.085 毫米，生成的影像大小為 2816 xx35842816 \times 3584 像素。所包含案例的影像已匿名處理並存儲在專用工作站中。
2.3. Study reading protocol and image analysis 2.3. 研究閱讀協議與影像分析
When the case collection was completed, two independent breast radiologists not involved neither in the population-based screening nor in the diagnostic work-up at any of the three centers, evaluated all images. The first reader (R1) had a 4 -years experience in breast imaging, including reading of screening mammograms; the second reader (R2) had a 6-years experience in clinical breast imaging. Both radiologists had clinical experience with DBT. 當病例收集完成後，兩位獨立的乳腺放射科醫生未參與任何三個中心的基於人群的篩檢或診斷工作，評估了所有影像。第一位讀者（R1）在乳腺影像學方面有 4 年的經驗，包括閱讀篩檢乳房 X 光檢查；第二位讀者（R2）在臨床乳腺影像學方面有 6 年的經驗。兩位放射科醫生均具備數位乳腺攝影（DBT）的臨床經驗。
Readers were blinded to the patients’ clinical data and reference standard, but aware of the source of the cases (regional screening program). For each case, readers had to evaluate first DM alone and subsequently DM in association with DBT. For both reading modalities (DM alone and DM with DBT), readers were asked to evaluate the images as if they were performing the reading in a screening population, and to state whether the examination presented a finding that prompted recall or not. Readers could evaluate only the current images, as no previous studies were made available. No computer aided detection system for DM or DBT was used. 讀者對患者的臨床數據和參考標準保持盲目，但知道病例的來源（區域篩檢計劃）。對於每個病例，讀者必須首先評估單獨的 DM，然後評估與 DBT 相關的 DM。對於這兩種閱讀模式（單獨的 DM 和帶 DBT 的 DM），讀者被要求評估圖像，就像他們在篩檢人群中進行閱讀一樣，並說明檢查是否出現促使召回的發現。讀者只能評估當前的圖像，因為沒有提供先前的研究。未使用任何計算機輔助檢測系統來進行 DM 或 DBT。
Breast density was evaluated by one of the readers (R1) according to the fifth edition of the BI-RADS ^(R){ }^{R}, distinguishing four classes: aa (breasts almost entirely fatty), bb (scattered areas of fibroglandular density), cc (breasts heterogeneously dense), and dd (extremely dense breasts) [7]. 乳腺密度由其中一位讀者（R1）根據第五版的 BI-RADS ^(R){ }^{R} 進行評估，區分為四個類別： aa （幾乎完全脂肪的乳房）、 bb （散在的纖維腺體密度區域）、 cc （乳房異質性密集）、以及 dd （極度密集的乳房）[7]。
2.4. Reference standard 2.4. 參考標準
The reference standard was the histopathological evaluation of needle biopsy sample or of surgical specimen for lesions classified as suspicious after complete work up. In the cases in which biopsy was not performed, reference standard was follow up of at least 1 year. Negative multiple assessment was considered as reference standard for patients lost at follow up. The multiple assessment consisted of additional mammographic views, ultrasonography (US) and, when available, comparison with previous examinations. In some cases, magnetic resonance imaging (MRI) was also performed, in order to exclude malignancy. 參考標準是對於經過完整檢查後被分類為可疑的病變進行的針刺活檢樣本或手術標本的組織病理學評估。在未進行活檢的情況下，參考標準為至少 1 年的隨訪。對於在隨訪中失聯的患者，負面多重評估被視為參考標準。多重評估包括額外的乳腺攝影視圖、超聲檢查（US），以及在可用的情況下，與先前檢查的比較。在某些情況下，還進行了磁共振成像（MRI），以排除惡性腫瘤。
2.5. Statistical analysis and sample size calculation 2.5. 統計分析與樣本大小計算
Cases that were assessed as negative or benign at multiple assessment, with or without biopsy, and remained stable at follow up, were considered true negative when the patient was not recalled by the study reader, false positive when the study reader prompted recall. Cases were assessed as true positive when a patient with a malignant lesion was recalled, and false negative when the reader did not prompt recall. 在多次評估中被評估為陰性或良性的病例，無論是否進行活檢，並且在隨訪中保持穩定，當患者未被研究讀者召回時被視為真正陰性，當研究讀者提示召回時則被視為假陽性。當一名患有惡性病變的患者被召回時，病例被評估為真正陽性，而當讀者未提示召回時則被視為假陰性。
The number of cases recalled by each reader with DM alone was used as reference number to calculate reduction in recall rate when DBT was added. This calculation was made first for both readers separately and then for the two readers together (double reading, DR ). When results of DR were calculated, both recalls prompted by only one or by both readers were considered. 每位僅有糖尿病（DM）的讀者所回憶的案例數量被用作參考數字，以計算當加入數位乳腺攝影（DBT）時回憶率的降低。這一計算首先是針對兩位讀者分別進行，然後再針對兩位讀者一起進行（雙重閱讀，DR）。在計算 DR 的結果時，僅由一位或兩位讀者促發的回憶都被考慮在內。
Diagnostic performance was estimated in terms of sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV), together with their 95%95 \% confidence interval ( 95%CI95 \% \mathrm{CI} ), calculated according the binomial distribution. 診斷性能的評估包括敏感性、特異性、準確性、陽性預測值（PPV）和陰性預測值（NPV），以及它們的 95%95 \% 信賴區間（ 95%CI95 \% \mathrm{CI} ），根據二項分佈計算。
The comparison between the two readers in terms of performance and recall rate at DM alone and DM+DBT was evaluated using McNemar test. The comparison of recall rates for DR was also estimated according to breast density, using Chi-square test. Inter-reader agreement was estimated using Cohen kappa\kappa coefficient. 兩位讀者在僅使用 DM 和 DM+DBT 的表現及回憶率方面的比較，使用 McNemar 檢驗進行評估。根據乳腺密度，DR 的回憶率比較也使用卡方檢驗進行估算。讀者間的一致性使用 Cohen kappa\kappa 係數進行估算。
The study was prospectively designed and the sample size calculation was based on the capability to show a 30%30 \% reduction (from the current 5%5 \% to 3.5%3.5 \% ) of the recall rate of DM + DBT compared to 該研究是前瞻性設計，樣本大小的計算基於能夠顯示 DM + DBT 的召回率從目前的 5%5 \% 降低到 3.5%3.5 \% 的 30%30 \% 的能力
Corresponding author at: Department of Biomedical Imaging and Imageguided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna/General Hospital Vienna, Waehringer Guertel 18-20, Vienna, Austria. 通訊作者：維也納醫科大學/維也納總醫院生物醫學影像與影像導向治療系，分子與性別影像部，Waehringer Guertel 18-20，維也納，奧地利。