Tackling “Small” Breast Cancer in Ultrasonography: What Are They and Why Does Screening Them Help?

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YING WANG, Danru Liu, Ping Xu, Lina Fu, Hong Ding This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4936095/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The study defined a group of “small” breast cancer (BC) detected at ultrasonography (US) and investigated the pathological nature of these small BC. We also explored factors associated with their recurrence and metastasis. Supplementary diagnosis with mammography was also considered. Methods This retrospective study included 491 BC patients pathologically confirmed with tumor size ≤ 10mm on US from January 2012 to December 2023; the study was approved by the institutional review board. We used chi-squared and unpaired independent t-tests to compare carcinoma in situ, including microinvasion (CIS) and invasive carcinoma regarding clinic, pathologic, US, and mammography characteristics. The characteristics associated with recurrence and metastasis were analyzed using univariate and multivariate Cox proportional hazard regression analysis. Results The analysis of 491 patients found that: for CIS, those with calcification were likely to be diagnosed by mammography (P < 0.001); for invasive cancers, those with unclear margins, irregular shapes and more color flow were likely to be diagnosed by US (all P < 0.005). 409 (83.9%) of the 491 patients received US follow-up with a median of 46 months. 17 of the 409 patients (4.2%) experienced recurrences, metastasis, or both. Women aged 40 years or younger and patients with invasive ductal carcinoma had the highest hazard rates for recurrence and metastasis (all P < 0.046). Conclusions For small BC, the sizes evaluated by US and pathology were partially in consistence. US diagnosis of invasive cancer had a relatively higher diagnostic rate, while mammography was advantageous in diagnosing CIS. Breast cancer Ultrasonography Mammography Small cancer Invasive carcinoma Figures Figure 1 Figure 2 Figure 3 Introduction The recent 10 years (2010–2019) saw an annual increase of 0.5% in the incidence rates of breast cancer (BC) in the United States; in contrast, BC mortality rates have declined annually by 1.3% from 2011 to 2020[ 1 ]. BC screening and advances in treatment contributed to these reductions in BC mortality[ 2 ]. Popular screening methods include mammography, magnetic resonance imaging (MRI), and ultrasonography (US). Mammography is the most common screening technique due to its simplicity and speed. However, women with dense breasts need supplemental BC screenings even with negative mammography results because mammography has trouble distinguishing breast density, an independent risk factor for BC development[ 3 – 5 ]. MRI is the most accurate method with high sensitivity, but the high cost, complex equipment, long inspection time and other factors limit MRI for routine screening in China. US is generally used for BC screening or regular follow-up in China due to its noninvasiveness, convenience, and low cost. Moreover, US has significant advantages in diagnosing breast nodules. This is why this study chose US as its focus. We chose a particular group of tumors on US for this study based on the staging system by AJCC, first published in 1977 based on the TNM concept[ 6 , 7 ]. This T classification of the primary tumor is the same based on clinical or pathologic criteria, or both; in general, however, pathologic determination of T size should take precedence over clinical determination. According to these guidelines, all T1mi, a, b, and c tumors are considered small tumors [ 8 ]. Most small tumors have good prognosis and they allow for breast conserving therapy for BC. Therefore, early detection of small tumors is very important for BC diagnosis and therapy. Invasive BC with T size less than or equal to10mm belongs to the early stage of breast cancer (less than T1b stage)[ 9 ] and these BC on US are hence chosen as the focus of this study. Although US has advantages in diagnosing breast nodules, it still has difficulty in diagnosing BC smaller than 10mm[ 10 – 12 ]. Pathologically confirmed small BC (less than 10mm) US may be misdiagnosed by US as benign or inconsistent with pathology results. Therefore, it is of great importance to analyze the US characteristics of small BC. In this paper, the clinical and pathological characteristics of BC less than 10mm diagnosed by US were analyzed and compared with mammography screening in order to help the diagnosis and management of small BC. Materials and methods Patients This study followed the Declaration of Helsinki and was approved by our institutional ethics committee (HIRB No. 2022 − 924). Eight thousand eight hundred and sixty-one BC patients were operated on and pathologically confirmed between January 2012 and December 2023 in our institution. Each BC patient underwent US examination prior to operation. Patients with tumor size less than or equal to 10mm according to sonograms by US were included in the study. A total of 491 patients (mean age, 56 years; age range, 28–84 years) were enrolled in this retrospective study. Due to the retrospective nature of the study, each patient who participated in the study waived informed consent. US examination US examinations were performed and interpreted by experienced certified US doctors with training in breast imaging using 6–18 MHz transducers (ATL 3000, Sequoia 512, Hitachi EUB-7500, Siemens Acuson S2000, Toshiba 550, Hitachi Vision Preirus, Hitachi EZN-MT30-S, and Supersonic Aixplorer). The US reports and images were reviewed to determine US characteristics such as size, shape, echo etc., US BI-RADS (Breast Imaging Reporting and Data System) categories, and armpit findings through our hospital US archiving and communication system. US BI-RADS categories were defined by the American College of Radiology (ACR). When two or more BC were identified, the largest lesions were recorded. The lesions with BI-RADS categories 0, 4A, 4B, 4C, and 5 were considered as different possible malignancies. BC lesions more than 10mm on US were excluded from our study. Mammography examination, clinic history and pathologic results All mammography examinations included four views (i.e., right axis view, right oblique view, left axis view, and left oblique view). They were performed and interpreted by experienced radiologists before operation. BI-RADS category was defined by ACR. The lesions with BI-RADS categories 0, 4A, B, C, and 5 were considered as different possible malignancies. All pathological results are diagnosed and reviewed by experienced pathologists after surgery. All examinations, clinical histories and pathologic results, including molecular typing (receptor status such as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2(HER-2) positive or negative was defined as the previous article)[ 13 – 15 ], can be reviewed in our hospital medical record reporting system. Follow-up Follow-up was performed from January 2012 to December 2023 using the images and reports of all subsequent US examinations in patients with BC through our hospital US archiving and communication system. The US instruments used were the same as those used for US examinations mentioned above, which were provided in our hospital. The post-surgery follow-up protocols involved physical examinations, mammography, computed tomography (CT) of the chest or abdomen, and whole-body fluorine 18 fluorodeoxyglucose positron emission tomography (PET)/CT. Clinical history, operation, and pathology records with follow-up were reviewed in our hospital medical record reporting system. Recurrence and metastasis are defined as the presence of in situ or invasive carcinoma on chest wall, breast, lymph node or other organs such as liver and lungs. A flowchart of the number of patients who were included and grouped is shown in Fig. 1 . Statistical analysis The optimal clinic, pathologic, US, and mammography characteristics were chosen to help differentiate carcinoma in situ, including microinvasion (CIS; note that CIS abbreviates carcinoma in situ including microinvasion) and invasive carcinoma. Chi-square tests were used to compare categorical variables. Unpaired independent t-tests were used to compare continuous variables and evaluated as mean values and standard deviation (SD) between CIS and invasive carcinoma. The size of US and pathology was also compared by unpaired independent t-tests. Comparison of the diagnostic rate of US, mammography, and the combination of the two for small BC was done using chi-squared tests. The combination of US and mammography was defined by diagnosing malignancy when either US or mammography classified BI-RADS 0, 4A, B, C, or 5. The follow-up time was defined as follows: for patients who experienced recurrence and metastasis, follow-up time was the interval between surgery and the discovery of in situ or invasive carcinoma on chest wall, lymph node, or other organs such as liver and lungs; for patients with no recurrence or metastasis, follow-up time was the interval between surgery and the latest follow-up. Kaplan Meier and Univariate Cox proportional hazard regression analysis were used to assess the association between categorical variables and recurrences and metastasis. Multivariate Cox proportional hazard regression analysis included the categorical variables that had statistical significance (P < 0.05) at univariate analysis. The predictable values of independent characteristics were assessed according to the hazard ratios (HRs). All analysis was performed using SPSS software (version 22; IBM, SPSS, Inc). A value of P < 0.05 was considered statistically significant. Results Initial patient characteristics The pathological results of the 491 patients were as follows: Ductal CIS (DCIS,105, 21.4%), Lobular CIS (LCIS, 4, 0.8%), DCIS and microinvasion (67, 13.6%), invasive ductal carcinoma (222, 45.2%), ductal and lobular invasive carcinoma (23, 4.7%), neuroendocrine carcinoma (6, 1.2%), papillary carcinoma (49, 10%), tubular carcinoma (6, 1.2%), mucinous carcinoma (6, 1.2%), apocrine carcinoma (2, 0.4%), and adenomyotic carcinoma (1, 0.2%). 345 of the 491 patients (70.3%) were LA positive. 48 of the 491 patients (9.8%) were ER, PR and HER-2 negative. Of the 491 patients with BC, 176 (35.8%) had CIS and 315 (64.2%) had invasive carcinoma. Comparison of CIS and invasive carcinoma CIS and invasive carcinoma can be distinguished using the characteristics of margin, shape, and color flow on US or calcification on mammography. Compared to CIS, a higher proportion of invasive cancers displayed unclear margins, irregular shapes, more color flow appearing on US (all P < 0.005, Table 1 and Fig. 2 ). On mammography, a significantly higher proportion of CIS had calcification (102/132 for CIS versus 118/206 for invasive cancers, P < 0.001). The initial patient characteristics are listed in Supplement Table 4. Table 1 Initial Patient Characteristics (n = 491) Characteristic CIS (n = 176) Invasive carcinoma (n = 315) P value Age 54 ± 11 57 ± 11 0.004 Accompanying changes 0.005 Yes 36 (7.3%) 35 (7.1%) No 140 (28.5%) 280 (57%) Tumor size at pathologic examination (mm, mean ± SD) Long diameter 6.0 ± 4.9 7.8 ± 3.8 < 0.001 Short diameter 5.0 ± 4.0 6.8 ± 3.4 < 0.001 Lymphovascular invasion 0.001 Absent 170 (34.6%) 277 (56.4%) Present 6 (1.2%) 38 (7.7%) Molecular typing 0.030 Her-2 positive; ER negative 16 (3.3%) 14 (2.9%) Her-2 positive; ER positive 11 (2.2%) 6 (1.2%) ER; PR; Her-2 negative 18 (3.7%) 30 (6.1%) Luminal A 117 (23.8%) 228 (46.4%) Luminal B 11 (2.2%) 32 (6.5%) PR positive 3 (0.6%) 5 (1.0%) Type of breast surgery 0.022 BCS 84 (17.1%) 117 (23.8%) Mastectomy 92 (18.7%) 198 (40.3%) Type of lymph node surgery < 0.001 Not cleared 60 (12.2%) 39 (7.9%) Cleared 85 (17.3%) 243 (49.5%) Sentinel lymph node biopsy 31 (6.3%) 33 (6.7%) Medical history 0.019 Palpable mass 38 (7.7%) 105 (21.4%) Spills 36 (7.3%) 41 (8.4%) Physical examination screening 99 (20.2%) 163 (33.2%) Pain 3 (0.6%) 6 (1.2%) US feature Tumor size at US (mm, mean ± SD) Long diameter 7.5 ± 2.0 8.1 ± 1.7 < 0.001 Short diameter 5.6 ± 2.0 6.5 ± 1.9 < 0.001 Margin < 0.001 Clear 103 (21.0%) 108 (22.0%) Unclear 73 (14.9%) 207 (42.2%) Shape < 0.001 Regular 78 (15.9%) 61 (12.4%) Irregular 98 (20.0%) 254 (51.7%) Color flow 0.005 Yes 95 (19.3%) 210 (42.8%) No 81 (16.5%) 105 (21.4%) Ductal dilatation 0.024 Yes 31 (6.3%) 33 (6.7%) No 145 (29.5%) 282 (57.4%) US BI-RADS < 0.001 Category 3 52 (10.6%) 35 (7.1%) Category 0,4A and above 124 (25.3%) 280 (57.0%) Calcification on Mammography < 0.001 Yes 102 (20.8%) 118 (24.0%) No 30 (6.1%) 88 (17.9%) Absent 44 (9.0%) 109 (22.2%) SD: standard deviation, BC: breast cancer, CIS: carcinoma in situ; DCIS: Ductal carcinoma in situ; LCIS: lobular carcinoma in situ; US: ultrasonography, BI-RADS: breast imaging reporting and data system, BCS: breast conservation surgery Comparison between US and pathological results Among 491 BC patients with nodules (long diameter ≤ 10mm) diagnosed by US, the pathological results of 401 (81.7%) showed nodules with a long diameter mean of 7.1 ± 4.3mm and a short diameter mean of 6.1 ± 3.8mm. US showed nodules with a long diameter mean of 7.9 ± 1.8mm and a short diameter mean of 6.2 ± 2.0mm. Although the long diameters measured by US and those measured by pathology were statistically different (P < 0.001), their averages were close and their ranges overlap noticeably; there was no statistically significant difference (P = 0.690) between the short diameters measured by US and those measured by pathology. In addition, the pathological results of 90 patients showed diffuse structures without boundaries, indicating no obvious nodular lesions. The pathological results of these 90 patients are as follows: DCIS (31, 34.4%), LCIS (3, 3.3%), DCIS and microinvasion (22, 24.4%), invasive ductal carcinoma (16, 17.8%), ductal and lobular invasive carcinoma (3, 3.3%), papillary carcinoma (12, 13.3%), tubular carcinoma (2, 2.2%), and apocrine carcinoma (1, 1.1%). Diagnosis by US, mammography and combined with them Of the 176 patients with CIS, 124 (70.5%) were suspected of malignancy by US. Only 132 patients (75%) out of these 176 also had mammograms. Among these 132 patients, 96 (72.7%) were suspected of malignancy by mammography. When US and mammography diagnosis was combined, the ability to suspect BC increased (158/176, 89.8%). Of the 315 patients with invasive carcinoma, 280 of 315 patients (88.9%) were the suspicions of malignancy by US. Only 206 patients (65.4%) out of these 315 also had mammograms. Among these 206 patients, 145 (70.4%) were suspected of malignancy by mammography. When US and mammography diagnosis was combined, the ability to diagnose BC increased (296/315, 94%). The chi-square tests comparing the abilities of US and mammography for diagnosing BC (P = 0.075) suggested that our data were sufficient to support an independence between US and mammography in diagnosing BC. The ability to diagnose BC increased when US and mammography were combined, and this improvement was dependent on both US and mammography (both P < 0.001). The diagnostic ratios of US, mammography, and their combination based on pathological types are shown in Table 2 . The accuracy of diagnosing CIS alone by mammography is higher than that by US, while the accuracy of diagnosing invasive cancer alone by US is higher than by mammography (Fig. 3 ). Table 2 The diagnostic ratios of US, mammography, and their combination based on pathological types Pathological types US mammography US and mammography DCIS 72/105 (68.6%) 53/77 (68.8%) 92/105 (87.6%) LCIS 1/4 (25%) 4/4 (100%) 4/4 (100%) DCIS and microinvasion 51/67 (76.1%) 39/51 (76.5%) 62/67 (92.5%) Invasive ductal carcinoma 202/222 (91%) 117/146 (80.1%) 215/222 (96.8%) Ductal and lobular invasive carcinoma 20/23 (87%) 6/16 (37.5%) 22/23 (95.7%) Neuroendocrine carcinoma 6/6 (100%) 3/3 (100%) 6/6 (100%) Papillary carcinoma 40/49 (81.6%) 15/32 (46.9%) 40/49 (81.6%) Tubular carcinoma 4/6 (66.7%) 2/4 (50%) 5/6 (83.3%) Mucinous carcinoma 6/6 (100%) 1/3 (33.3%) 6/6 (100%) Apocrine carcinoma 2/2(100%) 1/2 (50%) 2/2 (100%) Adenocystic carcinoma 0/1(0%) 0 (0%) 0/1 (0%) DCIS: Ductal carcinoma in situ; LCIS: lobular carcinoma in situ Characteristics of recurrence and metastasis patients There were 409 of 491 (83.9%) BC follow-up patients and the median follow-up time was 46 months. Of the 409 follow-up patients, 17 recurrences and metastasis (4.2%) were detected: 2 in the ipsilateral breast, 5 in the contralateral breast, 1 in the supraclavicular lymph node, 6 in the axillary lymph node, 1 in the chest wall, 1 in the chest cavity, and 1 in the bones. The clinical, pathologic, US, and mammography characteristics of the 17 patients with recurrence and metastasis are in Table 5 (see supplement) and Fig. 2 . Factors Associated with Recurrence and Metastasis As shown in Table 3 and Supplement Table 6, among all clinical, pathologic, US, and mammography characteristics, the factors associated with recurrence and metastasis were age (40 years or younger, P = 0.026) and pathological results (invasive carcinoma, P = 0.046). At the univariate cox proportional hazard regression analysis, age (40 years or younger) and pathological results (invasive carcinoma) were two independent factors. That is, women aged 40 years or younger or with pathological results showing invasive carcinoma had a higher hazard rate for recurrence and metastasis than those older than 40 years or with CIS and/or microinvasion. Moreover, invasive carcinoma in pathological results was ranked first in indicating recurrence and metastasis according to its hazard rate (HR 4.82). Table 3 Univariate Proportional Hazard Analysis of Factors Associated with Overall Recurrence and Metastasis in BC Patients with Follow up (n = 409) Characteristic Recurrence and Metastasis (n = 17) No Recurrence and Metastasis (n = 392) Hazard Ratio P value Age group 0.25 (0.08, 0.77) 0.015 ≤ 40 y 4 (1.0%) 29 (7.1%) > 40 y 13 (3.2%) 363 (88.8%) Pathologic results 4.82 (1.11, 21.15) 0.037 CIS and/or microinvasion 2 (0.5%) 142 (34.7%) Invasive carcinoma 15 (3.7%) 250 (61.1%) CIS: carcinoma in situ Discussion Small BC not only has relatively good prognosis, but also increases the possibility of breast conservation. According to TNM classification of the AJCC, small tumors are all considered as T1mi, a, b, or c tumors[ 9 ]. T1mi is a tumor that is 1mm or smaller. One study defined small tumors as tumors with tumor size ≤ 10mm (T1a, T1b)[ 16 ] and another study defined a group of small tumors by combining small diameter (≤ 10 mm, T1ab tumors) with low tumor cell proliferation (≤ 10% Ki67 expression rate)[ 17 ]. From the perspective of imaging examinations, screening BC less than 10mm is still difficult. Presently, enhanced MRI is the most reliable method to find small breast tumors when diagnosing BC[ 18 ]. US and mammography are still used to screen BC because of the long duration and high costs of MRI[ 19 ]. Although US has advantages in detecting BC nodules, previous research on small nodules with less than or equal to 10mm on US and clear BC pathology results are still insufficient[ 20 ]. In view of this, we chose to evaluate the significance of US and mammography screening using nodules with less than or equal to 10mm on US. Our results indicate that the size of BC diagnosed by US may not be completely consistent with pathological results. The most accurate size of tumor staging should be the pathological size. Imaging examination results can only be extremely close but cannot replace pathological examination results. Many studies that evaluate the accuracy of tumor size using mammography, US, and MRI by comparing them with pathological size find that these imaging methods can either under- or over-estimate tumor size[ 21 , 22 ]. Of the 491 BC patients with tumor size less than or equal to 10mm, 401 (81.7%) patients’ imaging results were consistent with pathological sizes (less than or equal to 10mm). For invasive cancer, US size results show little difference from the pathological size results; for in situ cancer that cannot be shown as a nodule or is diffusely displayed pathologically, US size values tend to be larger than pathological values. This result is consistent with the results reported in a previous literature[ 23 ], although the size range of BC selected in said previous literature is larger (4.5-38.1mm) and not limited to 10mm or less[ 23 ]. Other previous studies have found that imaging significantly underestimates the size of DCIS[ 24 ]. Even mammography is more accurate than US in measuring the maximum cancer diameter in DCIS of BC[ 25 ]. This may be why the 56 (62.2%) out of the 90 patients in our study who had inconsistent US and pathological results were diagnosed with CIS. Mammography and US should complement one another[ 26 ]. In this study, we found that mammography had advantages in the diagnosis of CIS based on the higher sensitivity and specificity of mammography in displaying fine calcification than US. According to previous literature reports, the morphology of calcification may indicate the possibility of cancer tissue [ 27 ]. BI-RADS classification is carried out by radiologists based on these characteristics. In the diagnosis of CIS, mammography has irreplaceable diagnostic value based on fine calcification. Mammography does have its own limitations. Previous studies have reported that Mammography has low sensitivity to small invasive breast cancer less than 15mm[ 28 ]. This result is consistent with our research findings. There is a fair number of false-negative mammograms[ 29 ]. Bae, M S et al. found that 81% of BC detected at screening US cannot be seen at all in mammography[ 30 ]. A study on Chinese women found that US is more sensitive and accurate than mammography[ 31 ]. Therefore, it is worth noting that US should not be replaced by mammography. US has more advantages in diagnosing nodular invasive cancer[ 32 ], even when the tumor size is very small. In our study, a higher proportion of invasive cancer appears on US with unclear margins, irregular shapes, more color flow; in particular, the higher proportion of color flow aligns with a previous study that found correlation between vascularization and breast cancer clarification[ 33 ]. It is consistent with a previous report that US can categorize BC into US-BI RADS categories according to sonogram characteristics such as margins, shapes and color flow. Nodular invasive cancer such as breast neuroendocrine carcinoma and mucinous carcinoma displays certain special characteristics on US - breast neuroendocrine carcinoma shows more irregular nodular changes without calcification and mucinous carcinoma shows more color flow. These characteristics gives US an advantage in their detection. In our study, cases of both types of carcinomas had 100% diagnostic rates (see Table 2 ), which may be evidence that the signature characteristics of these carcinomas make US an especially accurate method. However, it is worth noting that our study may not have enough cases to accurately represent diagnosis for these two types of carcinomas. US display of DCIS is not as good as that of invasive cancer due to the non-mass appearance of DCIS[ 34 ]. This also allows mammography, which is sensitive to fine calcification in CIS, to supplement the shortcomings of US. The detection of small high-grade invasive cancers is vital to reducing BC mortality. The mortality rate of BC has declined significantly in the past years. On the one hand, it is thanks to the progress of treatment level, yet on the other hand, it is thanks to early screening. According to 4 simulation models in a previous study, compared with interventions in 1975, BC screening and treatment in 2019 were associated with a 58% reduction in US BC mortality[ 35 ]. Previous literature has reported that multiple clinicopathological factors are associated with recurrence and metastasis of BC. For invasive breast cancer, factors associated with recurrence were age younger than 40 years, the triple-negative subtype, and BI-RADS category 4A lesions[ 36 ]. Locoregional recurrence occurred with different patterns according to BC subtypes, with younger patients having greater differences in patterns among subtypes than older patients[ 37 ]. Tumors with the same anatomic stage were assigned different prognostic stages depending on the histologic grade, hormone receptor status, HER2 status, and multigene panels[ 38 ]. In our study, women aged 40 years or younger or with pathological results showing invasive carcinoma had higher hazard rates for recurrence and metastasis than those older than 40 years or with CIS and/or microinvasion. This result is partially consistent with previous research findings above. There were several limitations to this study. Firstly, since this is a retrospective analysis of large-scale breast screenings, it must involve more than one breast US doctor. Although US-RADS provides a standard for analyzing US images and the participating breast US doctors are all senior and experienced US doctors, individual differences in analysis are still inevitable. Secondly, although there are relatively standardized treatment methods in this research process, there may still be individual differences in treatment during the study period that may affect prognostic factors. These factors may differ from the factors chosen in other reports. Moreover, this study did not include sufficient cases with long-term (> 120month years) follow-up. It is also worth noting that, in addition to traditional US, multimodal imaging such as contrast-enhanced US, elasticity, and even ABVS can provide more information to accurately diagnose BC. These additional imaging methods may also help prognosis and could be reflected in future research. Conclusions US diagnosis of invasive cancer had a high diagnostic rate because US is more sensitive in detecting small BC, whereas mammography shows advantages on CIS due to fine calcification in CIS. The recurrence and metastasis rate for small BC were far lower than that for large BC. The two factors independently associated with recurrence and metastasis of US-diagnosed small BC are age (40 years or younger) and pathology (invasive carcinoma). 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Finlayson CA, MacDermott TA. Ultrasound can estimate the pathologic size of infiltrating ductal carcinoma. Arch Surg. 2000;135(2):158–9. 10.1001/archsurg.135.2.158 . Liu RQ, Que J, Chen L, Dingee CK, Warburton R, McKevitt EC, et al. Measurements using mammography and ultrasonography underestimate the size of high-volume ductal carcinoma in situ. Am J Surg. 2021;221(6):1167–71. 10.1016/j.amjsurg.2021.03.043 . Wang Y, Wang J, Wang H, Yang X, Chang L, Li Q. Comparison of Mammography and Ultrasonography for Tumor Size of DCIS of Breast Cancer. Curr Med Imaging Rev. 2019;15(2):209–13. 10.2174/1573405614666180131163321 . Faguy K. Breast Sonography and Mammography: Complementarity and Correlation. Radiol Technol. 2017;89(1):M45–64. O'Grady S, Morgan MP. Microcalcifications in breast cancer: From pathophysiology to diagnosis and prognosis. Biochim Biophys Acta Rev Cancer. 2018;1869(2):310–20. 10.1016/j.bbcan.2018.04.006 . Blanks RG, Wallis MG, Alison RJ, Given-Wilson RM. An analysis of screen-detected invasive cancers by grade in the English breast cancer screening programme: are we failing to detect sufficient small grade 3 cancers? Eur Radiol. 2021;31(4):2548–58. 10.1007/s00330-020-07276-9 . Wadhwa A, Sullivan JR, Gonyo MB. Missed Breast Cancer: What Can We Learn? Curr Probl Diagn Radiol. 2016;45(6):402–19. 10.1067/j.cpradiol.2016.03.001 . Bae MS, Moon WK, Chang JM, Koo HR, Kim WH, Cho N, et al. Breast cancer detected with screening US: reasons for nondetection at mammography. Radiology. 2014;270(2):369–77. 10.1148/radiol.13130724 . Wang Y, Li Y, Song Y, Chen C, Wang Z, Li L, et al. Comparison of ultrasound and mammography for early diagnosis of breast cancer among Chinese women with suspected breast lesions: A prospective trial. Thorac Cancer. 2022;13(22):3145–51. 10.1111/1759-7714.14666 . Tadesse GF, Tegaw EM, Abdisa EK. Diagnostic performance of mammography and ultrasound in breast cancer: a systematic review and meta-analysis. J Ultrasound. 2023;26(2):355–67. 10.1007/s40477-022-00755-3 . Chen ST, Kuo SJ, Wu HK, Chen LS, Chen DR. Power Doppler breast ultrasound: association of vascularization and ER/c-erbB-2 co-expression in invasive breast carcinoma. Breast Cancer. 2013;20(2):152–8. 10.1007/s12282-011-0317-y . Watanabe T. Features of ductal carcinoma in situ ultrasound images. J Med Ultrason (2001). 2023;50(3):347–50. 10.1007/s10396-023-01334-7 . Caswell-Jin JL, Sun LP, Munoz D, Lu Y, Li Y, Huang H, et al. Analysis of Breast Cancer Mortality in the US-1975 to 2019. JAMA. 2024;331(3):233–41. 10.1001/jama.2023.25881 . Gordon PB, Berg WA, Jankowitz RC. Breast Cancer Recurrence after Initial Detection with Screening US. Radiology. 2017;285(3):1054–5. 10.1148/radiol.2017171849 . Cheun JH, Kim HK, Moon HG, Han W, Lee HB. Locoregional Recurrence Patterns in Patients With Different Molecular Subtypes of Breast Cancer. JAMA Surg. 2023;158(8):841–52. 10.1001/jamasurg.2023.2150 . Koh J, Kim MJ. Introduction of a New Staging System of Breast Cancer for Radiologists: An Emphasis on the Prognostic Stage. Korean J Radiol. 2019;20(1):69–82. 10.3348/kjr.2018.0231 . Supplementary Files supplementtable.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4936095","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":349003770,"identity":"586661d5-233e-482e-86b0-6f92d852cf89","order_by":0,"name":"YING WANG","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYNACAzjLhoefvYFoLcwgIk1GsucA0VaBtRy2MbjhQMD842cPv+YpuGO34Ub+wccFv87zMNxgYPzwMQePljN5adY8Bs+SN9xIZjae2Xebh3F2A7PkzG24tZgdyDEz5jE4nGx2I5lNmrfnNg+zzAE2Zl58Ws6/QdFyjodNIoGAlhs5xo+BWuzAWnh+HODhIaTF/sYbM8Y5BocT7M88NjbmbUjmkeA52IzXL5L9OcYf3vw5bC/ZnvjwMc8fO3v7480HP3zEowUI2KR4GBgSG0BMxjYw2YBXPRAwf/wBdCCE/YeQ4lEwCkbBKBiJAADG2lQMTgArxQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-5158-3133","institution":"Huashan Hospital Fudan University","correspondingAuthor":true,"prefix":"","firstName":"YING","middleName":"","lastName":"WANG","suffix":""},{"id":349003771,"identity":"5f64a059-feb9-40c8-b7b1-64c5cc08d179","order_by":1,"name":"Danru Liu","email":"","orcid":"","institution":"Huashan Hospital Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Danru","middleName":"","lastName":"Liu","suffix":""},{"id":349003772,"identity":"ca9d8598-f2ff-4366-8fd5-8f42e4211806","order_by":2,"name":"Ping Xu","email":"","orcid":"","institution":"Huashan Hospital Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Xu","suffix":""},{"id":349003773,"identity":"952c5555-ba52-4042-a5d3-83e3e05b3479","order_by":3,"name":"Lina Fu","email":"","orcid":"","institution":"Huashan Hospital Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Lina","middleName":"","lastName":"Fu","suffix":""},{"id":349003774,"identity":"00e2f046-131f-47c5-9a71-e0c93d86b876","order_by":4,"name":"Hong Ding","email":"","orcid":"https://orcid.org/0000-0002-9998-0904","institution":"Huashan Hospital Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Ding","suffix":""}],"badges":[],"createdAt":"2024-08-19 05:49:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4936095/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4936095/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67094024,"identity":"b4583802-3a76-4a02-9fb4-6f28bb32cb99","added_by":"auto","created_at":"2024-10-21 07:10:52","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":600696,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patients, specifically how patients with breast cancer with nodules less than 10mm (including 10mm) were included in the study\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4936095/v1/a760a35957badec2db2f7788.jpeg"},{"id":67092694,"identity":"355c6bf3-5968-40fd-8c89-928610d1cd8e","added_by":"auto","created_at":"2024-10-21 07:02:52","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":173392,"visible":true,"origin":"","legend":"\u003cp\u003eUltrasound images with breast cancer that had later undergone through recurrence and metastasis; arrows point to the cancer mass:\u003c/p\u003e\n\u003cp\u003ea and b. Longitudinal US images show 10*6mm oval hypoechoic mass (arrow) in 64-year-old woman with ductal dilatation in right breast at 9 o’clock position and close to the nipple. A small amount of blood flow signal is seen around the mass on the color Doppler. Lesion was assessed as BI-RADS category 4A. Surgery revealed solid papillary carcinoma.\u003c/p\u003e\n\u003cp\u003ec. Longitudinal US images show incident ipsilateral breast recurrence after 59 months.\u003c/p\u003e\n\u003cp\u003ed and e. Longitudinal US images show 10*5mm oval hypoechoic mass (arrow) in 40-year-old woman with suspicious calcification in left breast at 12 o’clock position after breast-conserving surgery of the right breast. A small amount of blood flow signal is seen around the mass on the color Doppler. Lesion was assessed as BI-RADS category 4A. Surgery revealed invasive breast cancer.\u003c/p\u003e\n\u003cp\u003ef. Longitudinal US images show swollen axillary lymph nodes after 30 months.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4936095/v1/8e3ffc4e5de53b60ca5b5db8.jpeg"},{"id":67092699,"identity":"93cbe6a0-22bb-4da5-a923-fe32b7afe518","added_by":"auto","created_at":"2024-10-21 07:02:53","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":478084,"visible":true,"origin":"","legend":"\u003cp\u003eBar graphs comparing the diagnosis of different breast cancer by US and mammography.\u003cstrong\u003e \u003c/strong\u003eUS shows a higher proportion of correct diagnosis for invasive cancer, but it is more apt to judge carcinoma in situ incorrectly as benign; mammography is relatively more competent in correctly diagnosing carcinoma in situ, but it has no obvious advantage in the diagnosis of invasive cancer.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4936095/v1/d3a0ed66045b5c424c880295.jpeg"},{"id":67094386,"identity":"7493fb31-12e7-48e2-bdd7-144ad17a0b28","added_by":"auto","created_at":"2024-10-21 07:18:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1909041,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4936095/v1/d369bb22-b96e-41cb-bd30-5d28583ce075.pdf"},{"id":67092696,"identity":"e2857bb4-c4cb-4227-b5c9-c88be79317da","added_by":"auto","created_at":"2024-10-21 07:02:52","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":40678,"visible":true,"origin":"","legend":"","description":"","filename":"supplementtable.docx","url":"https://assets-eu.researchsquare.com/files/rs-4936095/v1/5f137aeb37184b67aa60741b.docx"}],"financialInterests":"","formattedTitle":"Tackling “Small” Breast Cancer in Ultrasonography: What Are They and Why Does Screening Them Help?","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe recent 10 years (2010\u0026ndash;2019) saw an annual increase of 0.5% in the incidence rates of breast cancer (BC) in the United States; in contrast, BC mortality rates have declined annually by 1.3% from 2011 to 2020[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. BC screening and advances in treatment contributed to these reductions in BC mortality[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Popular screening methods include mammography, magnetic resonance imaging (MRI), and ultrasonography (US). Mammography is the most common screening technique due to its simplicity and speed. However, women with dense breasts need supplemental BC screenings even with negative mammography results because mammography has trouble distinguishing breast density, an independent risk factor for BC development[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. MRI is the most accurate method with high sensitivity, but the high cost, complex equipment, long inspection time and other factors limit MRI for routine screening in China. US is generally used for BC screening or regular follow-up in China due to its noninvasiveness, convenience, and low cost. Moreover, US has significant advantages in diagnosing breast nodules. This is why this study chose US as its focus.\u003c/p\u003e \u003cp\u003eWe chose a particular group of tumors on US for this study based on the staging system by AJCC, first published in 1977 based on the TNM concept[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This T classification of the primary tumor is the same based on clinical or pathologic criteria, or both; in general, however, pathologic determination of T size should take precedence over clinical determination. According to these guidelines, all T1mi, a, b, and c tumors are considered small tumors [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Most small tumors have good prognosis and they allow for breast conserving therapy for BC. Therefore, early detection of small tumors is very important for BC diagnosis and therapy. Invasive BC with T size less than or equal to10mm belongs to the early stage of breast cancer (less than T1b stage)[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and these BC on US are hence chosen as the focus of this study.\u003c/p\u003e \u003cp\u003eAlthough US has advantages in diagnosing breast nodules, it still has difficulty in diagnosing BC smaller than 10mm[\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Pathologically confirmed small BC (less than 10mm) US may be misdiagnosed by US as benign or inconsistent with pathology results. Therefore, it is of great importance to analyze the US characteristics of small BC. In this paper, the clinical and pathological characteristics of BC less than 10mm diagnosed by US were analyzed and compared with mammography screening in order to help the diagnosis and management of small BC.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis study followed the Declaration of Helsinki and was approved by our institutional ethics committee (HIRB No. 2022\u0026thinsp;\u0026minus;\u0026thinsp;924). Eight thousand eight hundred and sixty-one BC patients were operated on and pathologically confirmed between January 2012 and December 2023 in our institution. Each BC patient underwent US examination prior to operation. Patients with tumor size less than or equal to 10mm according to sonograms by US were included in the study. A total of 491 patients (mean age, 56 years; age range, 28\u0026ndash;84 years) were enrolled in this retrospective study. Due to the retrospective nature of the study, each patient who participated in the study waived informed consent.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eUS examination\u003c/h2\u003e \u003cp\u003eUS examinations were performed and interpreted by experienced certified US doctors with training in breast imaging using 6\u0026ndash;18 MHz transducers (ATL 3000, Sequoia 512, Hitachi EUB-7500, Siemens Acuson S2000, Toshiba 550, Hitachi Vision Preirus, Hitachi EZN-MT30-S, and Supersonic Aixplorer). The US reports and images were reviewed to determine US characteristics such as size, shape, echo etc., US BI-RADS (Breast Imaging Reporting and Data System) categories, and armpit findings through our hospital US archiving and communication system. US BI-RADS categories were defined by the American College of Radiology (ACR). When two or more BC were identified, the largest lesions were recorded. The lesions with BI-RADS categories 0, 4A, 4B, 4C, and 5 were considered as different possible malignancies. BC lesions more than 10mm on US were excluded from our study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eMammography examination, clinic history and pathologic results\u003c/h2\u003e \u003cp\u003eAll mammography examinations included four views (i.e., right axis view, right oblique view, left axis view, and left oblique view). They were performed and interpreted by experienced radiologists before operation. BI-RADS category was defined by ACR. The lesions with BI-RADS categories 0, 4A, B, C, and 5 were considered as different possible malignancies. All pathological results are diagnosed and reviewed by experienced pathologists after surgery. All examinations, clinical histories and pathologic results, including molecular typing (receptor status such as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2(HER-2) positive or negative was defined as the previous article)[\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], can be reviewed in our hospital medical record reporting system.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up\u003c/h2\u003e \u003cp\u003eFollow-up was performed from January 2012 to December 2023 using the images and reports of all subsequent US examinations in patients with BC through our hospital US archiving and communication system. The US instruments used were the same as those used for US examinations mentioned above, which were provided in our hospital. The post-surgery follow-up protocols involved physical examinations, mammography, computed tomography (CT) of the chest or abdomen, and whole-body fluorine 18 fluorodeoxyglucose positron emission tomography (PET)/CT. Clinical history, operation, and pathology records with follow-up were reviewed in our hospital medical record reporting system. Recurrence and metastasis are defined as the presence of in situ or invasive carcinoma on chest wall, breast, lymph node or other organs such as liver and lungs. A flowchart of the number of patients who were included and grouped is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe optimal clinic, pathologic, US, and mammography characteristics were chosen to help differentiate carcinoma in situ, including microinvasion (CIS; note that CIS abbreviates carcinoma in situ including microinvasion) and invasive carcinoma. Chi-square tests were used to compare categorical variables. Unpaired independent t-tests were used to compare continuous variables and evaluated as mean values and standard deviation (SD) between CIS and invasive carcinoma. The size of US and pathology was also compared by unpaired independent t-tests. Comparison of the diagnostic rate of US, mammography, and the combination of the two for small BC was done using chi-squared tests. The combination of US and mammography was defined by diagnosing malignancy when either US or mammography classified BI-RADS 0, 4A, B, C, or 5.\u003c/p\u003e \u003cp\u003eThe follow-up time was defined as follows: for patients who experienced recurrence and metastasis, follow-up time was the interval between surgery and the discovery of in situ or invasive carcinoma on chest wall, lymph node, or other organs such as liver and lungs; for patients with no recurrence or metastasis, follow-up time was the interval between surgery and the latest follow-up.\u003c/p\u003e \u003cp\u003eKaplan Meier and Univariate Cox proportional hazard regression analysis were used to assess the association between categorical variables and recurrences and metastasis. Multivariate Cox proportional hazard regression analysis included the categorical variables that had statistical significance (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) at univariate analysis. The predictable values of independent characteristics were assessed according to the hazard ratios (HRs).\u003c/p\u003e \u003cp\u003eAll analysis was performed using SPSS software (version 22; IBM, SPSS, Inc). A value of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eInitial patient characteristics\u003c/h2\u003e \u003cp\u003eThe pathological results of the 491 patients were as follows: Ductal CIS (DCIS,105, 21.4%), Lobular CIS (LCIS, 4, 0.8%), DCIS and microinvasion (67, 13.6%), invasive ductal carcinoma (222, 45.2%), ductal and lobular invasive carcinoma (23, 4.7%), neuroendocrine carcinoma (6, 1.2%), papillary carcinoma (49, 10%), tubular carcinoma (6, 1.2%), mucinous carcinoma (6, 1.2%), apocrine carcinoma (2, 0.4%), and adenomyotic carcinoma (1, 0.2%). 345 of the 491 patients (70.3%) were LA positive. 48 of the 491 patients (9.8%) were ER, PR and HER-2 negative. Of the 491 patients with BC, 176 (35.8%) had CIS and 315 (64.2%) had invasive carcinoma.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eComparison of CIS and invasive carcinoma\u003c/h2\u003e \u003cp\u003eCIS and invasive carcinoma can be distinguished using the characteristics of margin, shape, and color flow on US or calcification on mammography. Compared to CIS, a higher proportion of invasive cancers displayed unclear margins, irregular shapes, more color flow appearing on US (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.005, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). On mammography, a significantly higher proportion of CIS had calcification (102/132 for CIS versus 118/206 for invasive cancers, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The initial patient characteristics are listed in Supplement Table\u0026nbsp;4.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eInitial Patient Characteristics (n\u0026thinsp;=\u0026thinsp;491)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCIS (n\u0026thinsp;=\u0026thinsp;176)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eInvasive carcinoma\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;315)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAccompanying changes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (7.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (7.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e140 (28.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e280 (57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size at pathologic examination (mm, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLong diameter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShort diameter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphovascular invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbsent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e170 (34.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e277 (56.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (1.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecular typing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHer-2 positive; ER negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (2.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHer-2 positive; ER positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (1.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER; PR; Her-2 negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (3.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (6.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLuminal A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e117 (23.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e228 (46.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLuminal B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (6.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (0.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (1.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of breast surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84 (17.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e117 (23.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92 (18.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e198 (40.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of lymph node surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot cleared\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (12.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (7.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCleared\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85 (17.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e243 (49.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSentinel lymph node biopsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (6.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedical history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePalpable mass\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105 (21.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpills\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (7.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (8.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical examination screening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e99 (20.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e163 (33.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (0.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (1.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUS feature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size at US (mm, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLong diameter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShort diameter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMargin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e103 (21.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e108 (22.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (14.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e207 (42.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShape\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78 (15.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61 (12.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIrregular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e98 (20.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e254 (51.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eColor flow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95 (19.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e210 (42.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81 (16.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105 (21.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuctal dilatation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (6.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e145 (29.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e282 (57.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUS BI-RADS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (10.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (7.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory 0,4A and above\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e124 (25.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e280 (57.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCalcification on Mammography\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e102 (20.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e118 (24.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (6.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88 (17.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbsent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (9.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e109 (22.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eSD: standard deviation, BC: breast cancer, CIS: carcinoma in situ; DCIS: Ductal carcinoma in situ; LCIS: lobular carcinoma in situ; US: ultrasonography, BI-RADS: breast imaging reporting and data system, BCS: breast conservation surgery\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eComparison between US and pathological results\u003c/h2\u003e \u003cp\u003eAmong 491 BC patients with nodules (long diameter\u0026thinsp;\u0026le;\u0026thinsp;10mm) diagnosed by US, the pathological results of 401 (81.7%) showed nodules with a long diameter mean of 7.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3mm and a short diameter mean of 6.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8mm. US showed nodules with a long diameter mean of 7.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8mm and a short diameter mean of 6.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0mm. Although the long diameters measured by US and those measured by pathology were statistically different (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), their averages were close and their ranges overlap noticeably; there was no statistically significant difference (P\u0026thinsp;=\u0026thinsp;0.690) between the short diameters measured by US and those measured by pathology.\u003c/p\u003e \u003cp\u003eIn addition, the pathological results of 90 patients showed diffuse structures without boundaries, indicating no obvious nodular lesions. The pathological results of these 90 patients are as follows: DCIS (31, 34.4%), LCIS (3, 3.3%), DCIS and microinvasion (22, 24.4%), invasive ductal carcinoma (16, 17.8%), ductal and lobular invasive carcinoma (3, 3.3%), papillary carcinoma (12, 13.3%), tubular carcinoma (2, 2.2%), and apocrine carcinoma (1, 1.1%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDiagnosis by US, mammography and combined with them\u003c/h2\u003e \u003cp\u003eOf the 176 patients with CIS, 124 (70.5%) were suspected of malignancy by US. Only 132 patients (75%) out of these 176 also had mammograms. Among these 132 patients, 96 (72.7%) were suspected of malignancy by mammography. When US and mammography diagnosis was combined, the ability to suspect BC increased (158/176, 89.8%).\u003c/p\u003e \u003cp\u003eOf the 315 patients with invasive carcinoma, 280 of 315 patients (88.9%) were the suspicions of malignancy by US. Only 206 patients (65.4%) out of these 315 also had mammograms. Among these 206 patients, 145 (70.4%) were suspected of malignancy by mammography. When US and mammography diagnosis was combined, the ability to diagnose BC increased (296/315, 94%).\u003c/p\u003e \u003cp\u003eThe chi-square tests comparing the abilities of US and mammography for diagnosing BC (P\u0026thinsp;=\u0026thinsp;0.075) suggested that our data were sufficient to support an independence between US and mammography in diagnosing BC. The ability to diagnose BC increased when US and mammography were combined, and this improvement was dependent on both US and mammography (both P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eThe diagnostic ratios of US, mammography, and their combination based on pathological types are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The accuracy of diagnosing CIS alone by mammography is higher than that by US, while the accuracy of diagnosing invasive cancer alone by US is higher than by mammography (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe diagnostic ratios of US, mammography, and their combination based on pathological types\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological types\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003emammography\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUS and mammography\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDCIS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72/105 (68.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53/77 (68.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e92/105 (87.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLCIS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/4 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/4 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4/4 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDCIS and microinvasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51/67 (76.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39/51 (76.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62/67 (92.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvasive ductal carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e202/222 (91%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e117/146 (80.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e215/222 (96.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuctal and lobular invasive carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20/23 (87%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6/16 (37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22/23 (95.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeuroendocrine carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6/6 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/3 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6/6 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePapillary carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40/49 (81.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15/32 (46.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40/49 (81.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTubular carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4/6 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/4 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5/6 (83.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucinous carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6/6 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/3 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6/6 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApocrine carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/2(100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/2 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/2 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenocystic carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0/1(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0/1 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eDCIS: Ductal carcinoma in situ; LCIS: lobular carcinoma in situ\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of recurrence and metastasis patients\u003c/h2\u003e \u003cp\u003eThere were 409 of 491 (83.9%) BC follow-up patients and the median follow-up time was 46 months. Of the 409 follow-up patients, 17 recurrences and metastasis (4.2%) were detected: 2 in the ipsilateral breast, 5 in the contralateral breast, 1 in the supraclavicular lymph node, 6 in the axillary lymph node, 1 in the chest wall, 1 in the chest cavity, and 1 in the bones. The clinical, pathologic, US, and mammography characteristics of the 17 patients with recurrence and metastasis are in Table\u0026nbsp;5 (see supplement) and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eFactors Associated with Recurrence and Metastasis\u003c/h2\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Supplement Table\u0026nbsp;6, among all clinical, pathologic, US, and mammography characteristics, the factors associated with recurrence and metastasis were age (40 years or younger, P\u0026thinsp;=\u0026thinsp;0.026) and pathological results (invasive carcinoma, P\u0026thinsp;=\u0026thinsp;0.046). At the univariate cox proportional hazard regression analysis, age (40 years or younger) and pathological results (invasive carcinoma) were two independent factors. That is, women aged 40 years or younger or with pathological results showing invasive carcinoma had a higher hazard rate for recurrence and metastasis than those older than 40 years or with CIS and/or microinvasion. Moreover, invasive carcinoma in pathological results was ranked first in indicating recurrence and metastasis according to its hazard rate (HR 4.82).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate Proportional Hazard Analysis of Factors Associated with Overall Recurrence and Metastasis in BC Patients with Follow up (n\u0026thinsp;=\u0026thinsp;409)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRecurrence and\u003c/p\u003e \u003cp\u003eMetastasis (n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo Recurrence and Metastasis (n\u0026thinsp;=\u0026thinsp;392)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHazard Ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.25 (0.08, 0.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;40 y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (1.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29 (7.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;40 y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13 (3.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e363 (88.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathologic results\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.82 (1.11, 21.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.037\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIS and/or microinvasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (0.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e142 (34.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvasive carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15 (3.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e250 (61.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eCIS: carcinoma in situ\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSmall BC not only has relatively good prognosis, but also increases the possibility of breast conservation. According to TNM classification of the AJCC, small tumors are all considered as T1mi, a, b, or c tumors[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. T1mi is a tumor that is 1mm or smaller. One study defined small tumors as tumors with tumor size\u0026thinsp;\u0026le;\u0026thinsp;10mm (T1a, T1b)[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and another study defined a group of small tumors by combining small diameter (\u0026le;\u0026thinsp;10 mm, T1ab tumors) with low tumor cell proliferation (\u0026le;\u0026thinsp;10% Ki67 expression rate)[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. From the perspective of imaging examinations, screening BC less than 10mm is still difficult. Presently, enhanced MRI is the most reliable method to find small breast tumors when diagnosing BC[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. US and mammography are still used to screen BC because of the long duration and high costs of MRI[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Although US has advantages in detecting BC nodules, previous research on small nodules with less than or equal to 10mm on US and clear BC pathology results are still insufficient[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In view of this, we chose to evaluate the significance of US and mammography screening using nodules with less than or equal to 10mm on US.\u003c/p\u003e \u003cp\u003eOur results indicate that the size of BC diagnosed by US may not be completely consistent with pathological results. The most accurate size of tumor staging should be the pathological size. Imaging examination results can only be extremely close but cannot replace pathological examination results. Many studies that evaluate the accuracy of tumor size using mammography, US, and MRI by comparing them with pathological size find that these imaging methods can either under- or over-estimate tumor size[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Of the 491 BC patients with tumor size less than or equal to 10mm, 401 (81.7%) patients\u0026rsquo; imaging results were consistent with pathological sizes (less than or equal to 10mm). For invasive cancer, US size results show little difference from the pathological size results; for in situ cancer that cannot be shown as a nodule or is diffusely displayed pathologically, US size values tend to be larger than pathological values. This result is consistent with the results reported in a previous literature[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], although the size range of BC selected in said previous literature is larger (4.5-38.1mm) and not limited to 10mm or less[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Other previous studies have found that imaging significantly underestimates the size of DCIS[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Even mammography is more accurate than US in measuring the maximum cancer diameter in DCIS of BC[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This may be why the 56 (62.2%) out of the 90 patients in our study who had inconsistent US and pathological results were diagnosed with CIS.\u003c/p\u003e \u003cp\u003eMammography and US should complement one another[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In this study, we found that mammography had advantages in the diagnosis of CIS based on the higher sensitivity and specificity of mammography in displaying fine calcification than US. According to previous literature reports, the morphology of calcification may indicate the possibility of cancer tissue [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. BI-RADS classification is carried out by radiologists based on these characteristics. In the diagnosis of CIS, mammography has irreplaceable diagnostic value based on fine calcification. Mammography does have its own limitations. Previous studies have reported that Mammography has low sensitivity to small invasive breast cancer less than 15mm[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. This result is consistent with our research findings. There is a fair number of false-negative mammograms[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Bae, M S et al. found that 81% of BC detected at screening US cannot be seen at all in mammography[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. A study on Chinese women found that US is more sensitive and accurate than mammography[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Therefore, it is worth noting that US should not be replaced by mammography.\u003c/p\u003e \u003cp\u003eUS has more advantages in diagnosing nodular invasive cancer[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], even when the tumor size is very small. In our study, a higher proportion of invasive cancer appears on US with unclear margins, irregular shapes, more color flow; in particular, the higher proportion of color flow aligns with a previous study that found correlation between vascularization and breast cancer clarification[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. It is consistent with a previous report that US can categorize BC into US-BI RADS categories according to sonogram characteristics such as margins, shapes and color flow.\u003c/p\u003e \u003cp\u003eNodular invasive cancer such as breast neuroendocrine carcinoma and mucinous carcinoma displays certain special characteristics on US - breast neuroendocrine carcinoma shows more irregular nodular changes without calcification and mucinous carcinoma shows more color flow. These characteristics gives US an advantage in their detection. In our study, cases of both types of carcinomas had 100% diagnostic rates (see Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), which may be evidence that the signature characteristics of these carcinomas make US an especially accurate method. However, it is worth noting that our study may not have enough cases to accurately represent diagnosis for these two types of carcinomas. US display of DCIS is not as good as that of invasive cancer due to the non-mass appearance of DCIS[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. This also allows mammography, which is sensitive to fine calcification in CIS, to supplement the shortcomings of US.\u003c/p\u003e \u003cp\u003eThe detection of small high-grade invasive cancers is vital to reducing BC mortality. The mortality rate of BC has declined significantly in the past years. On the one hand, it is thanks to the progress of treatment level, yet on the other hand, it is thanks to early screening. According to 4 simulation models in a previous study, compared with interventions in 1975, BC screening and treatment in 2019 were associated with a 58% reduction in US BC mortality[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious literature has reported that multiple clinicopathological factors are associated with recurrence and metastasis of BC. For invasive breast cancer, factors associated with recurrence were age younger than 40 years, the triple-negative subtype, and BI-RADS category 4A lesions[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Locoregional recurrence occurred with different patterns according to BC subtypes, with younger patients having greater differences in patterns among subtypes than older patients[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Tumors with the same anatomic stage were assigned different prognostic stages depending on the histologic grade, hormone receptor status, HER2 status, and multigene panels[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. In our study, women aged 40 years or younger or with pathological results showing invasive carcinoma had higher hazard rates for recurrence and metastasis than those older than 40 years or with CIS and/or microinvasion. This result is partially consistent with previous research findings above.\u003c/p\u003e \u003cp\u003eThere were several limitations to this study. Firstly, since this is a retrospective analysis of large-scale breast screenings, it must involve more than one breast US doctor. Although US-RADS provides a standard for analyzing US images and the participating breast US doctors are all senior and experienced US doctors, individual differences in analysis are still inevitable. Secondly, although there are relatively standardized treatment methods in this research process, there may still be individual differences in treatment during the study period that may affect prognostic factors. These factors may differ from the factors chosen in other reports. Moreover, this study did not include sufficient cases with long-term (\u0026gt;\u0026thinsp;120month years) follow-up. It is also worth noting that, in addition to traditional US, multimodal imaging such as contrast-enhanced US, elasticity, and even ABVS can provide more information to accurately diagnose BC. These additional imaging methods may also help prognosis and could be reflected in future research.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eUS diagnosis of invasive cancer had a high diagnostic rate because US is more sensitive in detecting small BC, whereas mammography shows advantages on CIS due to fine calcification in CIS. The recurrence and metastasis rate for small BC were far lower than that for large BC. The two factors independently associated with recurrence and metastasis of US-diagnosed small BC are age (40 years or younger) and pathology (invasive carcinoma). This information showed that US can help find small BC with invasive carcinoma and thereby decrease the possibility of recurrence and metastasis\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGiaquinto AN, Sung H, Miller KD, Kramer JL, Newman LA, Minihan A, et al. Breast Cancer Statistics, 2022. 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Korean J Radiol. 2019;20(1):69\u0026ndash;82. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3348/kjr.2018.0231\u003c/span\u003e\u003cspan address=\"10.3348/kjr.2018.0231\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Breast cancer, Ultrasonography, Mammography, Small cancer, Invasive carcinoma","lastPublishedDoi":"10.21203/rs.3.rs-4936095/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4936095/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eThe study defined a group of “small” breast cancer (BC) detected at ultrasonography (US) and investigated the pathological nature of these small BC. We also explored factors associated with their recurrence and metastasis. Supplementary diagnosis with mammography was also considered.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eThis retrospective study included 491 BC patients pathologically confirmed with tumor size ≤ 10mm on US from January 2012 to December 2023; the study was approved by the institutional review board. We used chi-squared and unpaired independent t-tests to compare carcinoma in situ, including microinvasion (CIS) and invasive carcinoma regarding clinic, pathologic, US, and mammography characteristics. The characteristics associated with recurrence and metastasis were analyzed using univariate and multivariate Cox proportional hazard regression analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eThe analysis of 491 patients found that: for CIS, those with calcification were likely to be diagnosed by mammography (P \u0026lt; 0.001); for invasive cancers, those with unclear margins, irregular shapes and more color flow were likely to be diagnosed by US (all P \u0026lt; 0.005). 409 (83.9%) of the 491 patients received US follow-up with a median of 46 months. 17 of the 409 patients (4.2%) experienced recurrences, metastasis, or both. Women aged 40 years or younger and patients with invasive ductal carcinoma had the highest hazard rates for recurrence and metastasis (all P \u0026lt; 0.046).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions \u003c/strong\u003eFor small BC, the sizes evaluated by US and pathology were partially in consistence. US diagnosis of invasive cancer had a relatively higher diagnostic rate, while mammography was advantageous in diagnosing CIS.\u003c/p\u003e","manuscriptTitle":"Tackling “Small” Breast Cancer in Ultrasonography: What Are They and Why Does Screening Them Help?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-21 07:02:47","doi":"10.21203/rs.3.rs-4936095/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5595d0ff-6fd8-48ff-94ac-0c223e06322e","owner":[],"postedDate":"October 21st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-21T07:02:50+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-21 07:02:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4936095","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4936095","identity":"rs-4936095","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}