Ultrasonic features of automated breast volume scanner (ABVS) and handheld ultrasound (HHUS) combined with molecular biomarkers in predicting axillary lymph node metastasis of clinical T1–T2 breast cancer

Introduction

According to the 2020 Global Cancer Statistics, female breast cancer has surpassed lung cancer in incidence, ranking first among all cancers worldwide (1), with a mortality rate of 6.9%, and thus represents a serious threat to women’s lives and health. The detection of axillary lymph node metastasis (ALNM) is the most important prognostic indicator in determining the N staging and treatment of patients with breast cancer. At present, sentinel lymph node biopsy (SLNB) is the standard method for determining the staging of the axillary lymph node (ALN) (2). Patients with negative sentinel lymph nodes do not undergo ALN dissection to avoid postoperative complications caused by axillary surgery (3). Therefore, evaluating the ALNM of breast cancer for guiding multidisciplinary treatment decisions is now considered to be the key role of axillary imaging.

Ultrasonography is the preferred imaging method for evaluating breast tumors and ALN (4). However, handheld ultrasound (HHUS) is associated with certain disadvantages, such as operator dependency and nonstandardized image storage. The automated breast volume scanner (ABVS) is a three-dimensional ultrasound imaging technology developed for breast examination. Its fully automated, full-breast, and three-dimensional imaging features provide clinicians with a more reliable, comprehensive, and repeatable noninvasive imaging system that can overcome operator dependency. Previous studies have confirmed that ABVS is equivalent to magnetic resonance imaging in the ability to measure tumor size (5-7).

Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and the Ki-67 index (the percentage of cells that are positive for Ki-67 as determined by immunostaining of the primary tumor), which affect the biological behavior of breast cancer cells (8), are widely acknowledged to be predictive and prognostic molecular biomarkers of breast cancer (9,10). Of these, the Ki-67 index, as a proliferation and prognostic marker, has been associated with recurrence risk (3). However, few studies have examined the combination of molecular markers with the ultrasonic characteristics of ABVS and HHUS for evaluating the features of primary lesions in breast cancer and for further predicting ALNM. This study thus aimed to analyze the ability of the ultrasonic features in ABVS and HHUS in combination with molecular biomarkers to predict ALNM in clinical T1–T2 breast cancer. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-23-956/rc).

Methods

Patients

From January 2013 to August 2021, 168 patients with clinical T1–T2 breast cancer confirmed by core needle biopsy and surgery and who had undergone preoperative HHUS and ABVS at Peking University First Hospital were enrolled in the study. All patients underwent ipsilateral SLNB or ALN core needle biopsy and were divided into metastatic and nonmetastatic groups based on the pathological results of the ALN. Complete sonographic, clinical, and pathological data were collected for the study, and retrospective case-control analysis was performed. The Medical Ethics Committee of Peking University First Hospital approved the study, waiving the requirement for informed consent due to the retrospective nature of the design. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Inclusion and exclusion criteria

The inclusion criteria for patients were as follows: (I) no clinical intervention (such as core needle biopsy and neoadjuvant chemotherapy) performed before patients underwent ABVS and HHUS examinations; (II) a solitary tumor; (III) a clinical stage of T1–T2; and (IV) complete ABVS, HHUS, clinical, and pathological data. Meanwhile, the exclusion criteria were as follows: (I) distal metastases; (II) multifocal or multicenter tumors; (III) bilateral breast cancer; and (IV) carcinoma in situ or mixed invasive carcinoma.

According to the inclusion and exclusion, 18 patients (32 breast lesions) were excluded while 168 patients (168 breast lesions) were included (Figure 1).

Figure 1 Flowchart of patient screening.

Apparatus and methods

The Acuson S2000 ABVS system (5–14 MHz; Siemens Healthineers, Erlangen, Germany) with a 14L5BV three-dimensional probe (frequency 5–14 MHz) with a flexible mechanical arm was used to scan the lateral, median, and medial views of the bilateral breast, and each side was scanned three times. Subsequently, HHUS examination was conducted by two radiologists, with 6–18 MHz high-frequency linear transducers (18L6HD; Siemens Healthineers). After scanning, the obtained images were transmitted to the processing system and reconstructed in three dimensions by the workstation. The largest section was selected to measure the length, width, and height of breast lesions, and then the tumor volume was derived (length × width × height). The tumor-skin distance was defined as the vertical distance from the front edge of the tumor to the skin surface. The tumor-nipple distance was defined as the distance of the medial border of the tumor to the nipple. In ABVS, the reconstructed coronal-plane of breast lesions was observed for “convergence sign”, the axial-plane and reconstructed sagittal-plane were observed for orientation (parallel to the skin, nonparallel to the skin), and posterior acoustic attenuation. All of the three planes were observed for microcalcification, shape [regular (oval, round), irregular], margin (circumscribed, noncircumscribed). Following this, a 18L6HD probe (frequency 6–18 MHz) was used in color Doppler flow imaging to determine the Adler blood flow grade (0–I, II–III). According to Adler blood flow grade (9), the blood flow signals were classified as follows: grade 0, absent flow signals; grade I, minimal, with 1–2 pixels of blood flow signals; grade II, moderate, with a main vessel and/or several small vessels; and grade III, marked, with 4 or more vessels visualized.

Sonographic data were independently analyzed and diagnosed by two radiologists with more than 5 years of working experience in an ultrasound department. Two senior radiologists with more than 15 years of work experience reviewed the reports. If there was a disagreement, a third radiologist with more than 15 years of experience was consulted to determine the final result.

Pathological results

The pathological results of breast cancer and the ALN were confirmed. The results of ER, PR, HER-2, and Ki-67 index were evaluated according to the immunohistochemistry. Positivity for ER or PR was defined as ≥1% of the tumor cell nuclei being immunoreactive (10), while positivity for HER-2 was defined as immunohistochemical staining 3+ or positivity in fluorescence in situ hybridization (11). The high status of Ki-67 was defined as ≥20% (12).

Statistical analysis

SPSS 26.0 software (IBM Corp., Armonk, NY, USA) was used to conduct statistical analysis. Continuous variables were tested for normality. Variables with a normal distribution are presented as the mean ± standard deviation, and the t-test was used to compare the two groups. Otherwise, the variables are expressed the median with interquartile range (IQR), with the nonparametric Mann-Whitney test being used for analysis. Categorical variables are expressed as the number of cases and percentage and were compared with the Chi-squared test or Fisher exact test. A P value <0.05 (two-sided test) was considered to indicate a statistically significant difference. Univariate and multivariate logistic regression analyses were used to screen the risk factors for predicting ALNM.

Results

After the inclusion and exclusion criteria were applied, 168 patients were enrolled in the study, with a mean age of 53.71±12.26 years (range, 23–87 years). Of these patients, 88 (88/168, 52.4%) had ALNM and 80 (80/168, 47.6%) did not. The mean age of the metastatic group was 51.56±10.40 years while that in the nonmetastatic group was 56.08±13.71 years (P=0.017).

The pathological types were analyzed, which indicated 148 (148/168, 88.1%) cases of invasive carcinoma of no special type (IC-NST), 15 (15/168, 8.9%) cases of invasive lobular carcinoma, 3 (3/168, 1.8%) cases of mucinous carcinoma, and 2 (2/168, 1.2%) cases of invasive micropapillary carcinoma.

We compared the metastatic group with the nonmetastatic group in terms of sonographic features and molecular biomarkers (Table 1). The mean tumor-skin distance in the metastatic group (0.50±0.29 cm) was shorter than that in the nonmetastatic group (0.62±0.32 cm), representing a statistically significant difference (P=0.011). ALNM was more likely to occur with breast cancer if the Adler blood flow grade was II–III (P=0.014). The median tumor size in the nonmetastatic group was 3.42 cm³ (IQR 1.54–8.57 cm³), while that in the metastatic group was 8.78 cm³ (IQR 3.55–24.70 cm³), representing a statistically significant difference (P<0.001). However, there were no significant differences in ER, PR, HER-2, Ki-67, tumor-nipple distance, convergence sign, microcalcification, margin, shape, orientation, or posterior acoustic attenuation between the two groups. The results are summarized in Figures 2,3.

Figure 2 An 80-year-old woman confirmed with IC-NST and ALNM via pathology. (A) ABVS axial-plane sonography revealed a hypoechoic mass with an ill-defined margin. The tumor-skin distance was 2.0 mm. (B) ABVS reconstructed coronal-plane sonography indicated that the tumor-nipple distance was 10.0 cm, the tumor size on ABVS was 1.7 cm × 1.7 cm × 1.5 cm, and microcalcification was present. (C) ABVS reconstructed sagittal-plane sonography showed an irregular shape. (D) Adler blood flow grade III. (E) Histopathological examination confirmed IC-NST; immunohistochemistry indicated the following: ER negative, PR negative, HER-2 negative, and Ki-67 ≥20% (hematoxylin and eosin, 200×). IC-NST, invasive carcinoma of no special type; ALNM, axillary lymph node metastasis; ABVS, automated breast volume scanner; ER, estrogen receptor; PR, progesterone receptor; HER-2, human epidermal growth factor receptor 2.

Figure 3 A 50-year-old woman confirmed with IC-NST and ALNM via pathology. (A) ABVS axial-plane sonography revealed a hypoechoic mass with a noncircumscribed margin and distortion of Cooper’s ligament. The tumor-skin distance was 2.2 mm. (B) ABVS reconstructed coronal-plane sonography indicated that the tumor-nipple distance was 7.0 cm, the tumor size on ABVS was 2.4 cm × 1.8 cm × 1.6 cm, and convergence sign was present. (C) ABVS reconstructed sagittal-plane sonography showed an irregular shape. (D) Adler blood flow grade III. (E) Histopathological examination confirmed IC-NST; immunohistochemistry indicated the following: ER positive, PR positive, HER-2 negative, and Ki-67 ≥20% (hematoxylin and eosin, 200×). IC-NST, invasive carcinoma of no special type; ALNM, axillary lymph node metastasis; ABVS, automated breast volume scanner; ER, estrogen receptor; PR, progesterone receptor; HER-2, human epidermal growth factor receptor 2.

Logistic regression analysis screened three independent risk factors for inclusion into the regression model: the tumor-skin distance [odds ratio (OR) =0.279; P=0.024], the Adler blood flow grade (OR =2.164; P=0.046), and the tumor size on ABVS (OR =1.033; P=0.002), (Table 2). The regression equation was as follows: Logit(P) = −0.198 − 1.275 × tumor-skin distance + 0.772 × Adler blood flow grade + 0.032 × tumor size on ABVS.

Discussion

The study showed that a smaller tumor-skin distance, a larger tumor size on ABVS, and the Adler blood flow grade of II–III were significantly associated with ALNM in clinical T1–T2 breast cancer and demonstrated certain clinical value in predicting the risk of ALNM.

HHUS is an important screening technique for breast examination and is widely used due to its noninvasiveness and convenience. However, HHUS is influenced by breast tissue elasticity and physician experience. In this regard, the objectivity and repeatability are relatively poor due to operator dependence, and measurement and evaluation are difficult to unify. ABVS is a technique that can effectively overcome these limitations. The image scanning of ABVS via a robotic arm provides standardization, with a minimum image layer spacing of 0.2 mm. Data measurements are then performed at the postprocessing workstation, where the three-dimensional reconstructed images can be zoomed and rotated, and the postprocessing workstation shows a minimum layer thickness of 0.5 mm, which makes ABVS one of the most reproducible measurement techniques (7,13). In addition, it allows for a retrospective review of the images after the ABVS examination has been obtained.

The tumor-skin distance is an independent predictor for ALNM, and a smaller tumor-skin distance is associated with a higher incidence of ALNM (14-16). This is consistent with the conclusion of this study. The tumor-skin distance in the metastatic group was 0.50±0.29 cm, which was significantly shorter than the 0.62±0.32 cm in the nonmetastatic group (P=0.011). Due to anatomy, there is abundant anastomosis between the subcutaneous and parenchymal lymphatic trunks and the breast skin, and the subcutaneous and parenchymal lymphatic trunks drain toward the axilla (17). The cutaneous lymphatic pathway is involved in the breast cancer ALNM pathway. Therefore, in assessing ALNM, the tumor-skin distance should be routinely measured. The tumor-skin distance can be a visualized as a quantitative parameter representing the infiltrative growth into the superficial fascial layer and even extending to the skin, with skin infiltration being an independent risk factor for ALNM.

The tumor-nipple distance is closely related to ALNM: the smaller the nipple-tumor distance is, the greater the risk of ALNM (14,18,19). However, Lewis et al. (20) suggest the opposite, reporting that the proximity to the nipple does not increase the risk of ALNM. Our findings are consistent with Lewis et al.’s study in that tumor proximity to the nipple was not associated with a higher incidence of ALNM. The branching and communicating lymphatic pattern, along with the corresponding superficial and deep lymphatic flow, suggest that the drainage to the ALN does not necessarily need to pass through the subareolar plexus (21).

Breast cancer with hypervascularity usually exhibits stronger invasiveness, which ALNM is prone to happen (22,23). The results of the study showed that tumors with Adler blood flow grade of II–III had a greater association with ALNM than did a grade of 0–I. It has been speculated that breast cancer is a vascular-dependent tumor, and its growth, invasion, and metastasis are closely related to vascularization. Although vascularization cannot directly lead to ALNM, the angiogenic factors produced by tumor cells can promote the formation of tumor blood vessels, thus enhancing the tumor cells’ invasiveness. Tumor angiogenesis indirectly promotes ALNM.

The size of breast tumors is closely related to ALNM (23-27). In our study, the median volume of breast tumors was 3.42 cm³ in the nonmetastatic group and 8.78 cm³ in the metastatic group, representing a statistically significant difference. The larger the breast tumor is, the higher the risk of ALNM. This relationship may be explained by the following hypothesis: the larger the breast cancer is, the greater the possibility of infiltration to the surrounding lymphatic vessels, which ultimately leads to a higher risk of ALNM.

There is inconclusive evidence regarding the relationship between Ki-67 and ALNM. It has been suggested that a high Ki-67 index is an independent risk factor for ALN (28-30). However, some research does not support this, with Ki-67 being reported as incapable of predicting ALNM at initial diagnosis (31). In another study, Ki-67 ≥14% was not associated with a higher rate of SLN metastasis (P=0.403) (32). Moreover, it has been argued that support for Ki-67 as a prognostic indicator of node-positive breast cancer is based on limited samples and largely inferred from studies in which most patients had node-negative breast cancer (33). In our study, Ki-67 ≥20% was not predictive of ALNM and was not significantly associated with ALNM. There were 69 (69/88, 78.4%) cases with a high Ki-67 index in the metastatic group and 63 (63/80, 78.8%) cases with a high Ki-67 index in the no metastasis group. Presumably, these discrepancies can be attributed to different breast cancer T-staging and Ki-67 cutoff values leading to different outcomes.

There are some limitations to this study that should be addressed. First, we employed a single-center, retrospective design and a relatively small sample size, and thus a degree of selection bias might have been introduced. Second, the skin can be divided into the epidermis and dermis, which the study did not measure in detail.

Conclusions

ABVS and HHUS parameters demonstrated value in predicting the risk of ALNM in T1–T2 breast cancer. The smaller the tumor-skin distance, the larger the tumor size on ABVS, moreover, the Adler blood flow grade of II–III was found to be significantly related to ALNM. Radiologists should pay more attention to certain factors, including whether the breast cancer extends to the skin, the size of the tumor, and the blood supply.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-23-956/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-956/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The Medical Ethics Committee of Peking University First Hospital approved the study, waiving the requirement for informed consent due to the retrospective nature of the design. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Hersh EH, King TA. De-escalating axillary surgery in early-stage breast cancer. Breast 2022;62:S43-9. [Crossref] [PubMed]
3. Burstein HJ, Curigliano G, Thürlimann B, Weber WP, Poortmans P, Regan MM, Senn HJ, Winer EP, Gnant M. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann Oncol 2021;32:1216-35. [Crossref] [PubMed]
4. Marino MA, Avendano D, Zapata P, Riedl CC, Pinker K. Lymph Node Imaging in Patients with Primary Breast Cancer: Concurrent Diagnostic Tools. Oncologist 2020;25:e231-42. [Crossref] [PubMed]
5. Schmachtenberg C, Fischer T, Hamm B, Bick U. Diagnostic Performance of Automated Breast Volume Scanning (ABVS) Compared to Handheld Ultrasonography With Breast MRI as the Gold Standard. Acad Radiol 2017;24:954-61. [Crossref] [PubMed]
6. van Egdom LSE, Lagendijk M, Heijkoop EHM, Koning AHJ, van Deurzen CHM, Jager A, van Lankeren W, Koppert LB. Three-dimensional ultrasonography of the breast; An adequate replacement for MRI in neoadjuvant chemotherapy tumour response evaluation? - RESPONDER trial. Eur J Radiol 2018;104:94-100. [Crossref] [PubMed]
7. D'Angelo A, Orlandi A, Bufi E, Mercogliano S, Belli P, Manfredi R. Automated breast volume scanner (ABVS) compared to handheld ultrasound (HHUS) and contrast-enhanced magnetic resonance imaging (CE-MRI) in the early assessment of breast cancer during neoadjuvant chemotherapy: an emerging role to monitoring tumor response? Radiol Med 2021;126:517-26. [Crossref] [PubMed]
8. Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, Ruddy K, Tsang J, Cardoso F. Breast cancer. Nat Rev Dis Primers 2019;5:66. [Crossref] [PubMed]
9. Adler DD, Carson PL, Rubin JM, Quinn-Reid D. Doppler ultrasound color flow imaging in the study of breast cancer: preliminary findings. Ultrasound Med Biol 1990;16:553-9. [Crossref] [PubMed]
10. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010;28:2784-95. [Crossref] [PubMed]
11. Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, Bilous M, Ellis IO, Fitzgibbons P, Hanna W, Jenkins RB, Press MF, Spears PA, Vance GH, Viale G, McShane LM, Dowsett M. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 2018;36:2105-22. [Crossref] [PubMed]
12. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B, Senn HJ. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 2013;24:2206-23. [Crossref] [PubMed]
13. Girometti R, Zanotel M, Londero V, Linda A, Lorenzon M, Zuiani C. Automated breast volume scanner (ABVS) in assessing breast cancer size: A comparison with conventional ultrasound and magnetic resonance imaging. Eur Radiol 2018;28:1000-8. [Crossref] [PubMed]
14. Ansari B, Morton MJ, Adamczyk DL, Jones KN, Brodt JK, Degnim AC, Jakub JW, Lohse CM, Boughey JC. Distance of breast cancer from the skin and nipple impacts axillary nodal metastases. Ann Surg Oncol 2011;18:3174-80. [Crossref] [PubMed]
15. Eom YH, Kim EJ, Chae BJ, Song BJ, Jung SS. The distance between breast cancer and the skin is associated with axillary nodal metastasis. J Surg Oncol 2015;111:824-8. [Crossref] [PubMed]
16. Bae MS, Shin SU, Song SE, Ryu HS, Han W, Moon WK. Association between US features of primary tumor and axillary lymph node metastasis in patients with clinical T1-T2N0 breast cancer. Acta Radiol 2018;59:402-8. [Crossref] [PubMed]
17. Pavlista D, Eliska O. Cutaneous and subcutaneous lymphatic drainage of the breast. Lymphology 2005;38:92-102.
18. Faisal M, Fathy H, Gomaa AMM, Abd-Elzaher H, Ahmed MAH, Sayed MG. Breast cancer involvement of the nipple-areola complex and implications for nipple-sparing mastectomies: a retrospective observational study in 137 patients. Patient Saf Surg 2019;13:15. [Crossref] [PubMed]
19. Yang J, Yang Q, Mukherjee A, Lv Q. Distance Between the Tumour and Nipple as a Predictor of Axillary Lymph Node Involvement in Breast Cancer. Cancer Manag Res 2021;13:193-9. [Crossref] [PubMed]
20. Lewis EI, Ozonoff A, Nguyen CP, Kim M, Slanetz PJ. Breast cancer close to the nipple: does this increase the risk of nodal metastasis at diagnosis? Can Assoc Radiol J 2011;62:209-14. [Crossref] [PubMed]
21. Salgado R, Aftimos P, Sotiriou C, Desmedt C. Evolving paradigms in multifocal breast cancer. Semin Cancer Biol 2015;31:111-8. [Crossref] [PubMed]
22. Guo Q, Dong Z, Zhang L, Ning C, Li Z, Wang D, Liu C, Zhao M, Tian J. Ultrasound Features of Breast Cancer for Predicting Axillary Lymph Node Metastasis. J Ultrasound Med 2018;37:1354-3. [Crossref] [PubMed]
23. Zhu AQ, Li XL, An LW, Guo LH, Fu HJ, Sun LP, Xu HX. Predicting Axillary Lymph Node Metastasis in Patients With Breast Invasive Ductal Carcinoma With Negative Axillary Ultrasound Results Using Conventional Ultrasound and Contrast-Enhanced Ultrasound. J Ultrasound Med 2020;39:2059-70. [Crossref] [PubMed]
24. Fujii T, Yajima R, Tatsuki H, Suto T, Morita H, Tsutsumi S, Kuwano H. Significance of lymphatic invasion combined with size of primary tumor for predicting sentinel lymph node metastasis in patients with breast cancer. Anticancer Res 2015;35:3581-4.
25. Akissue de Camargo Teixeira P, Chala LF, Shimizu C, Filassi JR, Maesaka JY, de Barros N. Axillary Lymph Node Sonographic Features and Breast Tumor Characteristics as Predictors of Malignancy: A Nomogram to Predict Risk. Ultrasound Med Biol 2017;43:1837-45. [Crossref] [PubMed]
26. Zhang H, Sui X, Zhou S, Hu L, Huang X. Correlation of Conventional Ultrasound Characteristics of Breast Tumors With Axillary Lymph Node Metastasis and Ki-67 Expression in Patients With Breast Cancer. J Ultrasound Med 2019;38:1833-40. [Crossref] [PubMed]
27. Choong WL, Evans A, Purdie CA, Wang H, Donnan PT, Lawson B, Macaskill EJ. Mode of presentation and skin thickening on ultrasound may predict nodal burden in breast cancer patients with a positive axillary core biopsy. Br J Radiol 2020;93:20190711. [Crossref] [PubMed]
28. Park D, Kåresen R, Noren T, Sauer T. Ki-67 expression in primary breast carcinomas and their axillary lymph node metastases: clinical implications. Virchows Arch 2007;451:11-8. [Crossref] [PubMed]
29. Yin Y, Zeng K, Wu M, Ding Y, Zhao M, Chen Q. The levels of Ki-67 positive are positively associated with lymph node metastasis in invasive ductal breast cancer. Cell Biochem Biophys 2014;70:1145-51. [Crossref] [PubMed]
30. Tong YY, Sun PX, Zhou J, Shi ZT, Chang C, Li JW. The Association Between Ultrasound Features and Biological Properties of Invasive Breast Carcinoma Is Modified by Age, Tumor Size, and the Preoperative Axilla Status. J Ultrasound Med 2020;39:1125-34. [Crossref] [PubMed]
31. Bevilacqua JL, Kattan MW, Fey JV, Cody HS 3rd, Borgen PI, Van Zee KJ. Doctor, what are my chances of having a positive sentinel node? A validated nomogram for risk estimation. J Clin Oncol 2007;25:3670-9. [Crossref] [PubMed]
32. Thangarajah F, Malter W, Hamacher S, Schmidt M, Krämer S, Mallmann P, Kirn V. Predictors of sentinel lymph node metastases in breast cancer-radioactivity and Ki-67. Breast 2016;30:87-91. [Crossref] [PubMed]
33. Andre F, Arnedos M, Goubar A, Ghouadni A, Delaloge S. Ki67--no evidence for its use in node-positive breast cancer. Nat Rev Clin Oncol 2015;12:296-301. [Crossref] [PubMed]