Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial.

BACKGROUND: Mammography is the only proven method for breast cancer screening that reduces mortality, although it is inaccurate in young women or women with dense breasts. We investigated the efficacy of adjunctive ultrasonography. METHODS: Between July, 2007, and March, 2011, we enrolled asymptomatic women aged 40-49 years at 42 study sites in 23 prefectures into the Japan Strategic Anti-cancer Randomized Trial (J-START). Eligible women had no history of any cancer in the previous 5 years and were expected to live for more than 5 years. Randomisation was done centrally by the Japan Clinical Research Support Unit. Participants were randomly assigned in 1:1 ratio to undergo mammography and ultrasonography (intervention group) or mammography alone (control group) twice in 2 years. The primary outcome was sensitivity, specificity, cancer detection rate, and stage distribution at the first round of screening. Analysis was by intention to treat. This study is registered, number UMIN000000757. FINDINGS: Of 72,998 women enrolled, 36,859 were assigned to the intervention group and 36,139 to the control group. Sensitivity was significantly higher in the intervention group than in the control group (91·1%, 95% CI 87·2-95·0 vs 77·0%, 70·3-83·7; p=0·0004), whereas specificity was significantly lower (87·7%, 87·3-88·0 vs 91·4%, 91·1-91·7; p<0·0001). More cancers were detected in the intervention group than in the control group (184 [0·50%] vs 117 [0·32%], p=0·0003) and were more frequently stage 0 and I (144 [71·3%] vs 79 [52·0%], p=0·0194). 18 (0·05%) interval cancers were detected in the intervention group compared with 35 (0·10%) in the control group (p=0·034). INTERPRETATION: Adjunctive ultrasonography increases sensitivity and detection rate of early cancers. FUNDING: Ministry of Health, Labour and Welfare of Japan.

Uniqueness of ductal carcinoma in situ of the breast concurrent with papilloma: implications from a detailed topographical and histopathological study of 50 cases treated by mastectomy and wide local excision.

AIMS: To clarify the diagnostic clues of ductal carcinomas in situ (DCIS) associated with papilloma and optimal clinical management of papilloma diagnosed on core needle biopsy (CNB). METHODS AND RESULTS: A total of 50 surgically resected cases were examined histopathologically and topographically. Thirty-nine cases (78%) spread in segmental fashion. Papilloma and DCIS were intermingled closely in 44 cases (88%), occupying the same areas in varying proportions from DCIS-predominant to papilloma-predominant. The two components occupied discrete areas and collided focally in six cases (12%). Most were non-high-grade. Cribriform and solid architectures with fibrovascular stroma were frequent. The cribriform pattern was unique, consisting of fused tubules separated by fibrovascular stroma. Intraductal myoepithelial cells were present to varying degrees in 40 cases (80%). In 38 cases (76%), points were identified where papilloma and DCIS coexisted or collided within a single lumen (CC point). Forty-eight cases (96%) had either intraductal myoepithelial cells or CC points, implying that DCIS and papilloma existed in the same duct system. Radiology showed segmental abnormalities in 83% of the available cases. CONCLUSIONS: Intraductal myoepithelial cells do not always guarantee benignity. Surgical resection is recommended for papilloma in CNB when radiology shows segmental abnormalities.

Representation of lesion similarity by use of multidimensional scaling for breast masses on mammograms.

Presentation of similar reference images can be useful for diagnosis of new lesions. A similarity map which can visually present the overview of the relationship between the lesions with different types may provide the supplemental information to the reference images. A new method for constructing the similarity map by multidimensional scaling (MDS) for breast masses on mammograms was investigated. Nine pathologic types were included; three regions of interests each from the nine groups were employed in this study. Subjective similarity ratings by expert readers were obtained for all possible 351 pairs of masses. Using the average ratings, MDS similarity map was created. Each axis of the MDS configuration was fitted by the linear model with 13 image features to reconstruct the similarity map. Dissimilarity based on the distance in the reconstructed space was determined and compared with the subjective rating. The MDS map consistently represented the similarity between cysts and fibroadenomas, invasive lobular carcinomas and scirrhous carcinomas, and ductal carcinomas in situ, solid-tubular carcinomas, and papillotubular carcinomas with the experts' data. The correlation between the average subjective ratings and the dissimilarities based on the distance in the reconstructed feature space was much greater (-0.87) than that of the dissimilarities based on the distance in the conventional feature space (-0.65). The new similarity map by MDS can be useful for visualizing the relationship between breast masses with different pathologic types. It has potential usefulness in selecting the similarity measures and providing the supplemental information.

JSUM ultrasound elastography practice guidelines: breast.

Ten years have passed since the first elastography application: Real-time Tissue Elastography™. Now there are several elastography applications in existence. The Quality Control Research Team of The Japan Association of Breast and Thyroid Sonology (JABTS) and the Breast Elasticity Imaging Terminology and Diagnostic Criteria Subcommittee, Terminology and Diagnostic Criteria Committee of the Japan Society of Ultrasonics in Medicine (JSUM) have advocated breast elastography classifications for exact knowledge and good clinical use. We suggest two types of classifications: the technical classification and the classification for interpretation. The technical classification has been created to use vibration energy and to make images, and also shows how to obtain a good elastic image. The classification for interpretation has been prepared on the basis of interpretation of evidence in this decade. Finally, we describe the character and specificity of each vender equipment. We expect the present guidelines to be useful for many physicians and examiners throughout the world.

The Japan Society of Ultrasonics in Medicine guidelines on non-mass abnormalities of the breast.

It is possible to appropriately diagnose non-mass abnormalities by elucidating ultrasound non-mass abnormality findings and sharing the concept. If non-mass abnormalities can be diagnosed early, the number of curable cases could increase, leading to fewer breast cancer deaths. The Japan Society of Ultrasonics in Medicine (JSUM) Terminology/Diagnostic Criteria Committee has classified non-mass abnormalities into five subtypes: hypoechoic area in the mammary gland, abnormalities of the ducts, architectural distortion, multiple small cysts, and echogenic foci without a hypoechoic area. We herein define the findings for each of these subtypes and present a summary of the JSUM guidelines on non-mass abnormalities of the breast generated based on those findings.

Validity of computed mean compressed fibroglandular tissue thickness and breast composition for stratification of masking risk in Japanese women.

BACKGROUND: The volumetric measurement system for mammographic breast density is a high-precision objective method for evaluating the percentage of fibroglandular tissue volume (FG%). Nonetheless, FG% does not precisely correlate with subjective visual estimation (SVE) and shows poor evaluation performance regarding masking risk in patients with comparatively thin compressed breast thickness (CBT), commonly found in Japanese women. We considered that the mean compressed fibroglandular tissue thickness (mCGT), which incorporates the CBT element into the evaluation of breast density, may better predict masking risk. METHODS: Volumetric measurements and SVEs were performed on mammograms of 108 breast cancer patients from our center. mCGT was calculated as the product of CBT and FG%. SVE was classified using the Breast Imaging-Reporting and Data System classification, 5th edition. Subsequently, the performance of mCGT, SVE, and FG% in predicting masking risk was estimated using the AUC. RESULTS: The AUC values of mCGT and SVE were 0.84 (95% confidence interval, 0.71-0.92) and 0.78 (0.66-0.86), respectively (P = 0.16). The AUC of the FG% was 0.65 (0.52-0.77), which was significantly lower than that of mCGT (P < 0.001). The sensitivity and specificity of mCGT in predicting negative detection were 89% and 71%, respectively; of SVE 83% and 61% (versus 72% and 57% with FG%), suggesting that mCGT was superior to FG% in both sensitivity and specificity, and comparable with SVE. CONCLUSIONS: Objective mCGT calculated from the volumetric measurement system will highly likely be useful in evaluating breast density and supporting visual assessment for masking risk stratification.

Topographical, morphological and immunohistochemical characteristics of carcinoma in situ of the breast involving sclerosing adenosis. Two distinct topographical patterns and histological types of carcinoma in situ.

AIM: To examine the histopathological features of 24 surgically resected carcinoma in situ (CIS) involving sclerosing adenosis (SA), with special reference to the topographical relationship between CIS and SA. METHODS AND RESULTS: In 13 (54%) lesions, CIS was entirely surrounded by SA (type A) and in 11 (46%), CIS involved SA at least focally but was not confined to the SA area (type B). The mean size of CIS in type B (30.45 mm) was significantly larger than in type A (18.00 mm). The mean size of SA in type A (39.46 mm) was significantly larger than in type B (19.54 mm). Most type A CIS were non-high-grade, and the oestrogen receptor (ER)(+)/progesterone receptor (PgR)(+)/HER2(-) immunophenotype predominated. Most type B CIS were high-grade and six (54%) were ER(-)/PgR(-). Most type A were bcl-2(+)/p53(-) in both SA and CIS areas, but two (18%) apocrine ductal CIS of type B were bcl-2(-)/p53(+) in both SA and CIS areas. Expression of ER and cyclin D1 in SA was not different from that of SA unassociated with cancer. CONCLUSIONS: Most CIS involving SA arises within SA and high-grade DCIS tends to grow beyond SA. Occasional CIS may arise outside SA and secondarily involve SA.

Can quantitative evaluation of mammographic breast density, "volumetric measurement", predict the masking risk with dense breast tissue? Investigation by comparison with subjective visual estimation by Japanese radiologists.

BACKGROUND: Sensitivity to detect breast cancer (BC) is not high in a dense breast due to masking in mammography. To evaluate the breast density, a volumetric measurement system has been recently developed that measures the percent fibroglandular tissue volume (percent FGV, hereafter termed as "FG%") to the breast volume (BV). This study was designed to investigate whether evaluation using FG% can accurately predict the masking risk by comparing with the current standard method of subjective visual estimation (SVE). METHODS: Using pre-biopsy mammograms of 114 cases histopathologically diagnosed with BC in our facility, SVE based on BI-RADS (5th edition) and volumetric measurements of FG% were conducted. Performance to predict the masking risk was evaluated using the area under the receiver operating characteristic curve (AUC). Relationship between these parameters and the masking risk was evaluated by the adjusted multivariate linear regression analysis. RESULTS: The AUC of SVE values was 0.742 (95% CI 0.641-0.822), while that of FG% was as significantly low as 0.560 (95% CI 0.427-0.685) (P = 0.0014). The SVE values correlated with the detection of BC in mammography (P = 0.0035), but there was no significant relationship with FG% (P = 0.74). The median BV and FGV were 313 cm3 (IQR 191-440) and 63 cm3 (IQR 44-102), respectively. The FGV was comparable to the data for Caucasian women reported in previous studies, but the BV was one-half of the previous data. CONCLUSION: The current volumetric measurement system to evaluate FG% to BV was found to be insufficient in the performance to predict the masking risk in Japanese women with relatively small-sized breasts.

Polygon method: A systematic margin assessment for breast conservation.

BACKGROUND: Radiation therapy (RT) for women with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery (BCS) may be overtreatment for some, especially for those in which DCIS is eradicated, and ipsilateral breast tumor recurrence (IBTR) risk approaches the contralateral breast cancer (CBC) level. The aim of this study was to clarify whether the polygon method, a new systematic method of en face (tangential, shaved) margin assessment, can identify a subset of DCIS that can be safely treated by BCS alone. METHODS: A key tool of the polygon method is an adjustable mold that prevents the "pancake phenomenon" (flattening) of breast tissue after surgical removal so that the specimen is fixed in the shape of a polygonal prism. This preanalytical procedure enables us to command a panoramic view of entire en face margins 3-5-mm deep from the real peripheral cut surfaces. Competing risk analysis was used to quantify rates of IBTR and CBC and to evaluate risk factors. RESULTS: From 2000 to 2013, we identified 146 DCIS patients undergoing BCS with a contralateral breast at risk. In 100 DCIS patients whose margin was negative by the polygon method, 5 IBTR (3 DCIS and 2 invasive ductal carcinoma [IDC]) and 10 CBC (6 DCIS and 4 IDC) cases were identified during a median follow-up of 7.6 years (range, 0.9-17.4). Five- and 10-year cumulative incidence rates were 3.0% and 5.3% for IBTR, and 7.1% and 13.3% for CBC, respectively. Thus, patients with a negative margin consistently showed at least twofold lower IBTR than CBC despite omission of RT. CONCLUSIONS: Japanese women classified with a negative margin by the polygon method show a very low risk of IBTR and account for approximately half of CBC cases. In this subset of DCIS patients, additional RT is not beneficial.

Serous papillary adenocarcinoma of the female genital organs and invasive micropapillary carcinoma of the breast. Are WT1, CA125, and GCDFP-15 useful in differential diagnosis?

Serous papillary adenocarcinoma of the female genital organs and invasive micropapillary carcinoma of the breast have close histologic similarities. Thus, when these cancers occur synchronously or metachronously in the same patient, it is difficult to determine the primary site. We examined 23 serous papillary adenocarcinomas (16 ovarian, 5 endometrial, and 2 peritoneal) and 37 invasive micropapillary carcinomas of the breast (12 pure and 25 mixed types) on immunohistochemical expression of Wilm's tumor antigen-1 (WT1), CA125, and gross cystic disease fluid protein-15 (GCDFP-15), which have been reported to be useful in the differential diagnosis of primary ovarian carcinomas versus metastatic breast cancer to the ovary. The positive rates of WT1, CA125, and GCDFP-15 in serous papillary adenocarcinomas were 78%, 78%, and 0%, respectively, and the corresponding rates in invasive micropapillary carcinomas were 3%, 40%, and 38%. The CA125-positive rate of invasive micropapillary carcinoma was higher than the rate reported for other types of breast carcinomas. We consider CA125 to be not always useful in the differential diagnosis of serous papillary adenocarcinoma and invasive micropapillary carcinoma. Although the positive rate of WT1 was significantly higher in serous papillary adenocarcinoma than in invasive micropapillary carcinoma, WT1 expression in endometrial serous papillary adenocarcinoma was infrequent (20%). WT1 and GCDFP-15 could be useful markers for the differential diagnosis of ovarian and peritoneal serous papillary adenocarcinoma versus breast invasive micropapillary adenocarcinoma. However, the availability of GCDFP-15 is limited because of the low positive rate of GCDFP-15 in invasive micropapillary carcinomas.

3-D reconstruction and virtual ductoscopy of high-grade ductal carcinoma in situ of the breast with casting type calcifications using refraction-based X-ray CT.

Stereomicroscopic observations of thick sections, or three-dimensional (3-D) reconstructions from serial sections, have provided insights into histopathology. However, they generally require time-consuming and laborious procedures. Recently, we have developed a new algorithm for refraction-based X-ray computed tomography (CT). The aim of this study is to apply this emerging technology to visualize the 3-D structure of a high-grade ductal carcinomas in situ (DCIS) of the breast. The high-resolution two-dimensional images of the refraction-based CT were validated by comparing them with the sequential histological sections. Without adding any contrast medium, the new CT showed strong contrast and was able to depict the non-calcified fine structures such as duct walls and intraductal carcinoma itself, both of which were barely visible in a conventional absorption-based CT. 3-D reconstruction and virtual endoscopy revealed that the high-grade DCIS was located within the dichotomatous branches of the ducts. Multiple calcifications occurred in the necrotic core of the continuous DCIS, resulting in linear and branching (casting type) calcifications, a hallmark of high-grade DCIS on mammograms. In conclusion, refraction-based X-ray CT approaches the low-power light microscopic view of the histological sections. It provides high quality slice data for 3-D reconstruction and virtual ductosocpy.

Diagnostic performance of digital breast tomosynthesis and full-field digital mammography with new reconstruction and new processing for dose reduction.

BACKGROUND: The main barrier to adoption of digital breast tomosynthesis (DBT) plus full-field digital mammography (FFDM) is radiation exposure dose. The purpose of this study was to evaluate the diagnostic performance of DBT plus FFDM, both with newly developed technology (nd), at a dose comparable to that of the conventional FFDM alone. METHODS: Nine hundred and thirteen participants were recruited from May 2014 to January 2016 consecutively. For each subject, the exposure setting for DBT(nd) + FFDM(nd) was also used for the conventional FFDM alone. Retrospective reader studies were performed: DBT(nd) + FFDM(nd) (142 cases, including 42 cancer cases) and conventional FFDM (258 cases, including 87 cancer cases). Eight radiologists provided Japanese categorizations and probability of malignancy independently. Diagnostic performance was assessed by comparing sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Two-sided P values were calculated. RESULTS: DBT(nd) + FFDM(nd) showed sensitivity and AUC significantly increased over the conventional FFDM (85.4 vs. 80.3%, P = 0.015 and 90.9 vs. 88.3%, P = 0.049) and specificity did not significantly increase (89.6 vs. 88.4%, P = 0.52). The mean glandular dose (MGD) difference of DBT(nd) + FFDM(nd) and conventional FFDM was not significant (difference - 0.11 mGy, P = 0.08). CONCLUSIONS: In this study population, DBT plus FFDM, both with newly developed technology, provided diagnostic performance improved over the conventional FFDM alone, even at comparable MGD.

Development of a fully automatic scheme for detection of masses in whole breast ultrasound images.

Ultrasonography has been used for breast cancer screening in Japan. Screening using a conventional hand-held probe is operator dependent and thus it is possible that some areas of the breast may not be scanned. To overcome such problems, a mechanical whole breast ultrasound (US) scanner has been proposed and developed for screening purposes. However, another issue is that radiologists might tire while interpreting all images in a large-volume screening; this increases the likelihood that masses may remain undetected. Therefore, the aim of this study is to develop a fully automatic scheme for the detection of masses in whole breast US images in order to assist the interpretations of radiologists and potentially improve the screening accuracy. The authors database comprised 109 whole breast US imagoes, which include 36 masses (16 malignant masses, 5 fibroadenomas, and 15 cysts). A whole breast US image with 84 slice images (interval between two slice images: 2 mm) was obtained by the ASU-1004 US scanner (ALOKA Co., Ltd., Japan). The feature based on the edge directions in each slice and a method for subtracting between the slice images were used for the detection of masses in the authors proposed scheme. The Canny edge detector was applied to detect edges in US images; these edges were classified as near-vertical edges or near-horizontal edges using a morphological method. The positions of mass candidates were located using the near-vertical edges as a cue. Then, the located positions were segmented by the watershed algorithm and mass candidate regions were detected using the segmented regions and the low-density regions extracted by the slice subtraction method. For the removal of false positives (FPs), rule-based schemes and a quadratic discriminant analysis were applied for the distribution between masses and FPs. As a result, the sensitivity of the authors scheme for the detection of masses was 80.6% (29/36) with 3.8 FPs per whole breast image. The authors scheme for a computer-aided detection may be useful in improving the screening performance and efficiency.

Detectability comparison of modes in dual-mode digital breast tomosynthesis.

BACKGROUND: The objectives of this study were: (1) to evaluate the detectability of full-field digital mammography (FFDM) plus dual-mode digital breast tomosynthesis (DBT) and compare it with that of FFDM alone and (2) to compare the detectability of high-resolution-mode (HR mode used with 40°-angle imaging, 100-µm pixel size, and higher dose) DBT with that of standard-mode (ST mode used with 15°-angle imaging, 150-µm pixel size, and lower dose) DBT for diagnostic evaluation. MATERIALS: The local Institutional Review Board approved this retrospective study of two different sets of cases. All participants gave written informed consent. FFDM and DBT images of 471 women who were recalled were acquired between August 2013 and October 2014. HR mode and ST mode were applied to 155 breasts and 157 breasts, respectively. The cases of both modes were selected randomly. Eight radiologists interpreted the images. The detectability for recall cases and for follow cases, and area under the receiver operating characteristic curve (AUC) were calculated. RESULTS: Adding DBT to FFDM significantly increased the detectability for recall cases and AUC relative to those of FFDM alone (HR mode 8.9 %; 95 % confidence interval (CI) 5.7, 15.0 %; P = 0.013 and 4.9 %; 95 % CI 2.1, 7.7 %; P = 0.001; ST mode 8.3 %; 95 % CI 4.1, 12.1 %; P = 0.007 and 2.9 %; 95 % CI 0.5, 5.3 %; P = 0.02), whereas the detectability for follow cases did not significantly differ. The AUC increase was significantly higher in HR mode than in ST mode (1.5 %; 95 % CI 0.5, 3.7 %; P = 0.023). CONCLUSION: Adding HR-mode or ST-mode DBT to FFDM significantly improved the detectability for diagnostic evaluation case.

Evaluation of new image processing conditions for digital mammograms from Fuji computed radiography.

PURPOSE: A new processing parameter (T-type parameter) setting for gray scale was developed to improve the image quality of digital mammograms. To clarify the usefulness of this parameter setting, we have evaluated the image quality of digital mammograms (hard copy images) processed with this parameter, and compared it with S/F mammography. MATERIAL AND METHODS: Mammograms were made under the same radiographic conditions by the S/F and FCR systems (type 1, S/F; type 2 and 3, FCR with new T-type parameters; type 4 and 5, FCR with conventional parameters). A total of 49 images from 10 cases was selected for evaluation testing. Evaluation items were the contrast visibility of mammary glands and adipose tissues together with their granularity and sharpness. Eleven medical doctors participated in evaluating the images. RESULTS: The FCR hard copy images processed with the T-type parameter settings were significantly preferred over the conventional S/F images for the contrast visibility of mammary glands and adipose tissue. As for the other items (except for granularity), the FCR hard copy images processed with the T-type parameter settings were subjectively evaluated as slightly better than or equal to the S/F images. In contrast, the conventional S/F images were significantly preferred over the FCR hard copy images processed with the conventional parameter settings. CONCLUSION: The image quality of FCR hard copy images processed with the T-type parameter settings was preferred over that of conventional S/F images as evaluated by medical doctors who specialized in mammography interpretation.

Breast mass classification on mammograms using radial local ternary patterns.

Textural features can be useful in differentiating between benign and malignant breast lesions on mammograms. Unlike previous computerized schemes, which relied largely on shape and margin features based on manual contours of masses, textural features can be determined from regions of interest (ROIs) without precise lesion segmentation. In this study, therefore, we investigated an ROI-based feature, namely, radial local ternary patterns (RLTP), which takes into account the direction of edge patterns with respect to the center of masses for classification of ROIs for benign and malignant masses. Using an artificial neural network (ANN), support vector machine (SVM) and random forest (RF) classifiers, the classification abilities of RLTP were compared with those of the regular local ternary patterns (LTP), rotation invariant uniform (RIU2) LTP, texture features based on the gray level co-occurrence matrix (GLCM), and wavelet features. The performance was evaluated with 376 ROIs including 181 malignant and 195 benign masses. The highest areas under the receiver operating characteristic curves among three classifiers were 0.90, 0.77, 0.78, 0.86, and 0.83 for RLTP, LTP, RIU2-LTP, GLCM, and wavelet features, respectively. The results indicate the usefulness of the proposed texture features for distinguishing between benign and malignant lesions and the superiority of the radial patterns compared with the conventional rotation invariant patterns.