乳房超音波在乳癌診療上的應用
― 台灣經驗 ―

               張金堅 侯明峰 黃俊升 郭文宏 歐陽賦

台灣乳癌有年輕化的特徵，由於乳房的密度相較於西方人較為緻密，乳房超音波的角色更為重要，為了釐清乳房超音波在乳房篩檢上的角色，針對40-49歲的婦女，規劃四年內乳房攝影及乳房超音波逐年交替進行的大型臨床試驗，整合19家醫學中心，預計邀請79691位婦女參加，23170位實際參與試驗組，參加率58%，參加者於次年的回診率可逹九成，在兩年的期中分析中，超音波檢查在第一輪篩檢對乳癌及其中的侵襲癌的檢出率分別是千分之2.22及1.87，第二輪篩檢的檢出率則降為分別是千分之1.69及1.09，超音波篩檢的成效整體而言略低於乳房攝影，透過二輪的的篩檢，不論第一年先行篩檢乳房超音波或乳房攝影，可發現無症狀乳癌檢出率可逹0.58%及0.51%，總結而言, 乳癌篩檢可早期診斷乳癌，乳房超音波在輔助角色上應有其地位。

    台灣的一些研究指出，以乳房超音波做為早期乳癌的篩檢工具較乳房X光攝影在準確度及效率上都有過之而無不及，因此，乳房超音波檢查在台灣一直被當作乳房檢查的重要工具，但良好乳房超音波影像需要多重因素的相互配合，缺一不可，包括：現代化專業的乳房超音波機、操作者熟練的技巧、標準的影像品管作業、至最後有經驗醫師的影像判讀以及與臨床症狀的配合。針對目前國內女性乳癌不斷升高的發生率與死亡率，乳房超音波的檢查日益頻繁，但是其報告品質的良莠不齊與標準不一，已降低臨床醫師對其信賴度，因此提升乳房超音波的品質已到了刻不容緩的地步。台灣乳房醫學會過去承接國民健康局辦理「乳房超音波品質提升及人員培訓計畫」已進行四年，過去四年在各位專家委員的努力，成立「乳房超音波影像品質管制委員會」，並著手制定各項規範，對參與計劃的醫院進行多次的抽審片，評估回饋其影像品質的評比，也透過不斷地教育訓練，以輔導的方式提升醫師判片的能力。參考國際間現行品管標準訂定「乳房超音波品管規範與執行要點」，引進美國的ACR BIRADS LEXCICON來進行乳房超音波的判讀，期待能仿效國外在乳房超音波的影像判讀建立一致的標準，避免過度診斷造成病人的憂慮，或者錯失潛在病灶。

    乳房超音波在鑑別腫瘤的良惡性多是根據腫瘤的邊界及外型，我們在先期研究中嘗試解析超音波的先端原始訊號，組合成Nakagami參數，參數中統計分析訊號的散射大小，形狀，或濃度。在最佳的ROC曲線下，區分腫瘤良惡性的診斷準確率為 81.4％，敏感性為 88.6％，特異性為 74.3％，未來可整合傳統的參數，進一步提昇乳房超音波診斷的正確性。
    最近乳癌的治療已進入量身訂作的時代，對於20~30%的晚期乳癌患者在接受新輔助化療後的病人，如何提供一項具實用性的臨床評估工具以預測臨床上治療的效果非常重要。吾人利用都卜勒超音波具有非侵襲性、經濟、可重複性及儀器普遍等優點。在系列的觀察中，我們發現有臨床反應的病人，腫瘤內部典型的血流密度變化是在接受化學治療的初期有明顯血管新生在達到頂點之後則血流密度再逐漸下降，這對新輔助化學治療的臨床實驗設計供了很重要的指引，一些決定性的變化可能發生在治療過程早期。我們研究設定兩個查核點，血流密度指數值增量超過5%或血流密度指數昇高的尖峰值(Peak VI)超過10%，對有經驗的超音波診斷醫師而言，這個幅度的血流密度增加或豐富性，即使在沒有電腦輔助的分析的協助下，也很容易憑藉肉眼察覺出來，根據這兩個查核點，即便在沒有分析軟體的協助下，也能預測化學治療的反應，大大提昇此種監測工具的臨床實用性。由於是發生在治療早期的變化，到達查核點的時間小於一個月，不必觀察太久，使這項監測具有實用性。在研究中所顯示的對化學治療有反應的患者，其初始的血流密度指數值較高的趨勢是十分明顯的現象，除了可以根據腫瘤的初始狀態預估化療可能的療效之外，也提供了血管是腫瘤生長所需之外，腫瘤週邊血管與藥物動力學應該也有密切關係，值得深入探究。

    乳房超音波除了可導引細針抽吸細胞檢查或粗針組織切片外，麥瑪通切片術可利用較粗的切片針在真空吸引的協助下對直徑小於2公分的腫瘤直接進行切除，在手術中可對於觸摸不到的腫瘤及乳房微鈣化的細針定位針幫忙進行定位，協助手術的順利進行；在乳癌患者的術後追踪方面，對於胸壁上、腋下及鎖骨上下淋巴結的局部復發和對側乳癌的早期偵測，也有很大的助益，這相關之臨床資料及結果將做詳細之分析與討論，並於大會中提出報告。

Application of Breast Ultrasound for Breast Cancer Diagnosis and Treatment

King-Jen Chang, Chang, Ming-Feng Hou, Chiun-Sheng Huang, Wen-Hung Kuo, Fu Ou-Yang

Breast cancer has been observed to affect younger demographics in Taiwan. Due to the greater breast density, compared to the Western population, the role of breast ultrasounds has become more important. In order to define the role of breast ultrasounds in breast screening, a large clinical trial has been conducted for women between 40 and 49 years of age in which mammogram and breast ultrasound were performed and alternated every other year for a trial period of four years. A total of 19 medical centers took part in this trial and 79,691 women were invited to participate. Eventually 23,170 subjects participated in the trial, generating a 58% participation rate. The return rate for the following year among participants was, however, as high as 90%. In the 2-year interim-analysis, the detection rate of breast cancer and invasive cancer for the first round screening performed with breast ultrasound was 2.22‰ and 1.87‰, respectively, and 1.69 ‰ and 1.09‰ for the second round of screening. Overall, the screening result of breast ultrasound was slightly inferior to that of the mammogram. It was discovered through two rounds of screening that, regardless of which test was performed first, the detection rate of asymptomatic breast cancer was 0.58% and 0.51%. To conclude, breast cancer screening can provide early diagnosis of breast cancer in which breast ultrasound plays a vital and auxiliary part.

Some studies in Taiwan suggest that the accuracy and efficiency of breast ultrasounds as a screening tool for early breast cancer diagnosis out-weighted those of the mammogram. As a result, breast ultrasounds have long been an important tool for breast exams in Taiwan. An excellent breast ultrasound image requires the combination of several equally important and indispensable factors, including: a modern and specialized breast ultrasound machine, well-trained and proficient operator, standardized quality control for images and the interpretation by experienced physicians and consistence of clinical symptoms. In view of the elevated morbidity and mortality rates of breast cancer in women in Taiwan, the number of breast ultrasound exams has been increasing steadily. However, unregulated report quality and inconsistent standards have reduced the credibility of clinical physicians. Consequently, improving the quality of breast ultrasounds has become a pressing issue.

The Breast Cancer Society of Taiwan has been commissioned by the Bureau of Health Promotion to organize the “Breast Ultrasound Quality Enhancement and Personnel Training Program” for 4 years. With the hard work of experts and committee members over the last 4 years, a Breast Ultrasound Image Quality Control Committee was established and relevant guidelines were stipulated to randomly review cases from hospitals participating in the program and to provide assessment and feedback on their image quality. The program also aims to improve the interpretation ability of physicians through a counseling approach and by providing continuous educational training. The Breast Ultrasound Quality Control Provisions and Guidelines were stipulated in reference to the current international quality control standards. The ACR BIRADS LEXICON was imported from the United States for the interpretation of breast ultrasounds in the hopes that a synchronized standard can be established for the interpretation of breast ultrasound images in the same fashion as other countries in order to prevent panic in patients due to misdiagnosis or overlooking potential lesions.

 Breast ultrasounds determine whether a tumor is benign or malignant based on the margin and morphology of the tumor. In an early study, we attempted to analyze the source signal of ultrasound wave to derive the Nakagami parameters and use the parameters to statistically analyze the scattering, pattern or intensity of signals. Under the optimal ROC curve, the diagnostic accuracy for distinguishing the nature of a tumor was 81.4%, with a sensitivity of 88.6% and specificity of 74.3%. In the future, conventional parameters can be integrated to further enhance the accuracy of breast ultrasound diagnosis.

 In the era of personalized breast cancer treatment, providing a practical clinical assessment tool to the 20~30% of advanced breast cancer patients who responded poorly to neoadjuvant chemotherapy will help predict the benefits of clinical treatment. The Doppler ultrasonography utilized has the advantages of being non-invasive, economical, having reproducible results and common instruments. It was discovered through a series of observations that in patients with clinical responses the typical blood density change in the tumor, there was gradual decline of blood density after the distinct angiogenesis in the early stages of chemotherapy reached the peak stage. Such a phenomenon provided a crucial guideline for the clinical trial design of neoadjuvant chemotherapy. Some decisive changes may happen during the early treatment which will only be noticed under a series of observations. The two checkpoints adopted here were an increment over 5% in the vascularization index or an increment over 10% in Peak VI. For an experienced ultrasound diagnosis doctor, such amplitude of VI increments or enhancements can be easily observed with the naked eye without the assistance of any computer-aided analysis. Based on these two checkpoints, all responses to chemotherapy can be predicted even without the assistance of any analysis software, which greatly enhanced the clinical application of such monitoring tools. Given that these changes occur early during treatment, the time before one of the checkpoints develops is under one month, which does not require an extensive observation time, making this tool more practicable on top of its applicability. It was a distinct phenomenon that patients responding to chemotherapy in the study tended to have a higher initial VI value. Not only can potential benefits of chemotherapy be predicted based on the tumor’s initial state, the phenomenon also demonstrated that blood was a requirement for tumor growth. It is likely that peripheral blood vessels surrounding the tumor may have a close association with pharmacodynamics, which is worthy of further investigation.

 Breast ultrasounds can guide fine-needle aspiration or core-needle biopsy. The Mammotome biopsy can utilize a thicker biopsy probe to perform direct resection on tumors with a diameter smaller than 2cm with the assistance of vacuum aspiration. During surgery, it enables the localization of impalpable breast tumor and guidance needle for breast microcalcification to facilitate a smooth procedure. In terms of the postoperative follow-up for breast cancer patients, it also helps the early detection of regional relapse in the chest wall, axillary and neck lymph nodes as well as contralateral breast cancer.