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Association of clinicopathologic and sonographic features with stromal tumor-infiltrating lymphocytes in triple-negative breast cancer

BMC Cancer volume 24, Article number: 997 (2024) Cite this article

Abstract

Background

Increased level of stromal tumor-infiltrating lymphocytes (sTILs) are associated with therapeutic outcomes and prognosis in triple-negative breast cancer (TNBC). This study aimed to investigate the associations of clinicopathologic and sonographic features with sTILs level in TNBC.

Methods

This study included invasive TNBC patients with postoperative evaluation of sTILs after surgical resection. Tumor shape, margin, orientation, echo pattern, posterior features, calcification, and vascularity were retrospectively evaluated. The patients were categorized into high-sTILs (≥ 20%) and low-sTILs (< 20%) level groups. Chi-square or Fisher’s exact tests were used to assess the association of clinicopathologic and sonographic features with sTILs level.

Results

The 171 patients (mean ± SD age, 54.7 ± 10.3 years [range, 22‒87 years]) included 58.5% (100/171) with low-sTILs level and 41.5% (71/171) with high-sTILs level. The TNBC tumors with high-sTILs level were more likely to be no special type invasive carcinoma (p = 0.008), higher histologic grade (p = 0.029), higher Ki-67 proliferation rate (all p < 0.05), and lower frequency of associated DCIS component (p = 0.026). In addition, the TNBC tumors with high-sTILs level were more likely to be an oval or round shape (p = 0.001), parallel orientation (p = 0.011), circumscribed or micro-lobulated margins (p < 0.001), complex cystic and solid echo patterns (p = 0.001), posterior enhancement (p = 0.002), and less likely to have a heterogeneous pattern (p = 0.001) and no posterior features (p = 0.002).

Conclusions

This preliminary study showed that preoperative sonographic characteristics could be helpful in distinguishing high-sTILs from low-sTILs in TNBC patients.

Peer Review reports

Introduction

Triple-negative breast cancer (TNBC) is characterized by no expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [1]. As a result of the lack of therapeutic molecular targets, TNBC is characterized by higher rates of recurrence and distant metastasis, and TNBC is considered one of the worst prognosis subtypes among all breast cancers [2].

In recent years, tumor-infiltrating lymphocytes (TILs) have been proven to be a robust biomarker for predicting treatment response and prognosis for breast cancer [3, 4]. Previous clinical trials have shown that patients with high-TILs breast cancer respond better to chemotherapy than low-TILs breast cancer [5, 6]. It is noted that TILs are most commonly in the TNBC subtype among all breast cancers [7, 8]. Several studies have demonstrated that TNBC patients with high-TILs have lower recurrence rates [9] and higher pathologic complete response rates than TNBC patients with low-TILs [10]. In addition, TNBC patients with high-TILs have been found to have an excellent survival, including recurrence-free survival, disease-free survival, and overall survival [11,12,13]. Currently, the quantification of TILs is visually assessed on hematoxylin and eosin (H&E)-stained pathological slides [3]. On H&E-stained pathological slides, TILs can be classified into stromal TILs (sTILs) and intratumoral TILs (iTILs) in breast cancer tissue. However, iTILs are less abundant than sTILs, which are challenging to differentiate from cell necrosis or apoptosis [14, 15]. Thus, the evaluation of sTILs is recommended by the guidelines of the International TILs Working Group on Breast Cancer [16]. In many cases, the quantification of sTILs is obtained through a core needle biopsy, especially in patients requiring neoadjuvant chemotherapy. However, several well-known pitfalls of core needle biopsy may affect the accuracy of evaluating sTILs level, such as limited tissue sampling and heterogeneity in lymphocyte distribution [17]. Due to allowing for visualization of the entire tumor, the imaging method may serve as a supplementary method for assessing sTILs level that may help overcome these limitations.

Ultrasonography is a crucial conventional imaging modality for breast cancer. In recent years, ultrasonography has been used to predict the sTILs level in invasive breast cancers. High-sTILs tumors have been found to show more circumscribed margins, round shape, heterogeneous echogenicity, and larger size in invasive breast cancers [18]. However, TNBC is defined as a specific subtype of breast cancer. On ultrasonography, invasive TNBC has sonographic features that are different from other non-TNBC invasive breast cancers but similar to benign breast lesions, including regular shape, no angular/spiculated margin, posterior acoustic enhancement, and no calcifications [19]. Up to now, the association of sonographic features and clinicopathologic features with postoperative sTILs level remains poorly investigated in invasive TNBC. Considering the pitfalls of sTILs evaluation through needle biopsy, in this study, we included the patients with surgically resected TNBC. This study aimed to investigate the associations of clinicopathologic and sonographic features with sTILs level in TNBC.

Materials and methods

The Institutional Review Board (IRB) of the Second Affiliated Hospital of Zhejiang University School of Medicine approved this retrospective study (authorization number: 2023 − 0300), and the requirement for written informed consent was waived. This study was completed in accordance with the Declaration of Helsinki as revised in 2013.

Patients selection

Among 3998 consecutive patients who underwent breast ultrasound examinations and were confirmed with pathological diagnosis of primary invasive breast cancer between January 2017 and December 2023, patients were excluded for the following reasons: (1) non-TNBC breast cancer proven by immunohistochemistry staining (n = 3640); (2) without sTILs evaluation (n = 85); (3) pathological evaluation using the needle biopsy specimen but not surgical resection specimens (n = 74); (4) underwent neoadjuvant chemotherapy in TNBC before surgical resection (n = 18); (5) preoperative breast ultrasound images lost (n = 10). After these exclusions, 171 TNBC patients with preoperative ultrasound and postoperative evaluation of sTILs were finally included. The flowchart of the patient enrolment process is shown in Fig. 1.

Fig. 1
figure 1

Flowchart of the patient enrollment process. TNBC, Triple-negative breast cancer; sTILs, stromal tumor-infiltrating lymphocytes

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Pathologic evaluation

ER, PR, and HER2 data were extracted from the pathology reports after surgical resection. Each surgical resection was performed within two weeks of the diagnostic ultrasound. The quantification of sTILs was obtained according to recommendations from the International Immuno-Oncology Biomarker Working Group in Breast Cancer [20]. The ratio of the lymphoid cells to stroma in each breast cancer tumor was recorded as a percentage [14]. Several recent studies identified the optimal cut-off value of 20% sTILs that was best associated with pathologic complete response in patients with TNBC [10, 21]. In this study, the patients were categorized into high-sTILs (≥ 20%) and low-sTILs (< 20%) level groups (Fig. 2).

Fig. 2
figure 2

(a) H&E staining showed a postoperative TNBC case with sTIL level of 85% (×40), and the case was categorized into high-sTILs (≥ 20%) group. (b) H&E staining showed a postoperative TNBC case with sTIL level of 5% (×40), and the case was categorized into low-sTILs (< 20%) level group. TNBC, Triple-negative breast cancer; sTILs, stromal tumor-infiltrating lymphocytes

Full size image

Ultrasound examination and feature evaluation

All breast ultrasound examinations were performed by experienced board-certified radiologists with ≥ 5 years’ experience in superficial tissue ultrasound imaging, such as breast, thyroid, and muscle. All breast ultrasound examinations were carried out on ultrasound machines, including ESAOTE (MyLab 90 X-vision, Italy), Aplio 500 (Toshiba Medical Systems, Tokyo, Japan), Logic E9 (GE Healthcare, Wauwatosa, USA), and Resona7 (Mindray, Shenzhen, China) with corresponding high-frequency probes. Transverse and longitudinal images of the index tumor were obtained during the ultrasound examinations. If there were multiple lesions, the largest tumor was regarded as the index tumor in the affected breast. Sonographic features of the index tumor for each patient were retrospectively evaluated by two radiologists with ≥ 5 years of experience in breast ultrasound, and they were blinded to the ultrasound reports and histopathologic results. In the case of a disagreement between the two observers, a consensus was arrived after discussion. Tumor shape, margin, orientation, echo pattern, posterior features, calcification, and vascularity were evaluated using the 5th edition ultrasound lexicon of the American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) Atlas.

Statistical analysis

Clinicopathologic and sonographic features between the low-sTILs and high-sTILs level groups were compared using a chi-square test or Fisher’s exact test for categorical variables and an independent t-test for continuous variables. The continuous variables were investigated using the Kolmogorov–Smirnov test to determine whether or not the distribution was normal. All statistical analyses were performed using SPSS software version 26.0 (IBM, USA), and p-value < 0.05 was considered a statistically significant difference.

Results

Clinicopathologic Features

In this study, a total of 171 women patients (mean ± SD age, 54.7 ± 10.3 years [range, 22‒87 years]) were finally included. The clinicopathologic features between the low-sTILs and high-sTILs level groups are summarized in Table 1. The high-sTILs level group, compared with the low-sTILs level group, was more likely to be invasive carcinoma no special type (NST) (NST in 64/71 [90.1%] vs. 74/100 [74%], p = 0.008), higher histologic grade (grade 3 in 54/71 [76.1%] vs. 59/100 [59%], p = 0.029), higher Ki-67 proliferation rate (≥ 14% in 68/71 [95.8%] vs. 86/100 [86%], p = 0.035; ≥20% in 68/71 [95.8%] vs. 83/100 [83%], p = 0.01; ≥30% in 64/71 [90.1%] vs. 78/100 [78%], p = 0.037), and lower frequency of associated ductal carcinoma in situ (DCIS) component (41/71[57.7%] vs. 74/100 [74%], p = 0.026). Patients’ age, pathologic size, multifocality, axillary lymph node metastasis, and lymphovascular invasion were not different between the low-sTILs and high-sTILs level groups (all p > 0.05).

Table 1 Clinicopathologic features among 171 patients with TNBC, stratified by sTILs level
Full size table

Sonographic features

The sonographic features between the low-sTILs and high-sTILs level groups are summarized in Table 2. Compared with the low-sTILs level, the TNBC tumors with high-sTILs level were more likely to be an oval or round shape (45/71[63.4%] vs. 38/100 [38%], p = 0.001), had a greater likelihood of having parallel orientation (62/71[87.3%] vs. 71/100 [71%], p = 0.011), circumscribed or micro-lobulated margins (33/71[46.5%] vs. 18/100 [18%], p < 0.001), were more likely to have complex cystic and solid echo patterns (9/71[12.7%] vs. 2/100 [2%], p = 0.001), less likely to have a heterogeneous pattern (3/71[4.2%] vs. 18/100 [18%], p = 0.001), more likely to have posterior enhancement (28/71[39.4%] vs. 16/100 [16%], p = 0.002) and less likely to have no posterior features (41/71[57.7%] vs. 80/100 [80%], p = 0.002). The calcification and vascularity were not different between the low-sTILs and high-sTILs level groups (all p > 0.05). Examples of TNBC tumors with low-sTILs and high-sTILs level are shown in Fig. 3.

Table 2 Sonographic features among 171 patients with TNBC, stratified by sTILs level
Full size table
Fig. 3
figure 3

(a) A 69-year-old woman with low-sTILs TNBC. Breast ultrasound reveals that the mass has an irregular shape with not parallel orientation and indistinct margin. (b) A 48-year-old woman with high-sTILs TNBC. Breast ultrasound shows that the mass has an oval shape with parallel orientation and circumscribed margin and posterior enhancement. TNBC, Triple-negative breast cancer; sTILs, stromal tumor-infiltrating lymphocytes

Full size image

Discussion

In this study, we investigated the associations of clinicopathologic and sonographic features with sTILs level in surgically resected TNBC. The sonographic analysis showed that compared with the TNBC tumors with low-sTILs level, the TNBC tumors with high-sTILs level were more likely to have an oval or round shape, parallel orientation, circumscribed or microlobulated margins, complex cystic and solid echo patterns, and posterior enhancement; less likely to have a heterogeneous pattern and no posterior features. In addition, the clinicopathologic analysis showed that compared with the TNBC tumors with low-sTILs level, the TNBC tumors with high-sTILs level were more likely to be NST invasive carcinoma, higher histologic grade, higher Ki-67 proliferation rate, and had a lower frequency of associated DCIS component.

To the best of our knowledge, four studies have explored the association between sTILs level and sonographic features of breast cancer [18, 22,23,24]. However, these studies included patients in different molecular subtypes of breast cancer. Fukui et al. and Celebi et al. included all the molecular subtypes of breast cancer (only a few TNBC patients) [18, 22], Lee et al. included the patients with HER2-positive breast cancer [24], and Candelaria et al. included the patients with TNBC [23]. However, in Candelaria et al.’s study, the evaluation of sTILs level for each case was from a core needle biopsy specimen; thus, the sample obtained was not wholly representative of the tumor and the surrounding stroma [23]. Evaluation of sTILs level using biopsy specimens has several well-known pitfalls that may affect the accuracy of evaluating sTILs level, such as limited tissue sampling and heterogeneity in lymphocyte distribution [17]. In addition, evaluation of sTILs level from the entire tumor specimens after surgical resection is more effective than core needle biopsy specimens [8, 25, 26]. To overcome this shortcoming, in this study, we only included the TNBC patients with the evaluation of sTILs from surgical resection specimens, and we excluded the TNBC patients with the assessment of sTILs from the needle biopsy specimen. Our study is the first to investigate the associations between sonographic characteristics and sTILs level in surgically resected TNBC. Despite using different specimens, the present study and Candelaria et al.’s study both showed that high-sTILs level was associated with oval or round tumor shape, tumor margins, complex cystic and solid echo patterns, and posterior acoustic enhancement in TNBC patients [23]. In contrast to Candelaria et al.’s study [23], our study revealed a statistically significant association between high-sTILs level and parallel orientation.

Using the pathological evaluation of the surgical specimens, we found that compared with the TNBC tumors with low-sTILs level, the TNBC tumors with high-sTILs level were more likely to manifest with an oval or round tumor shape, circumscribed margin, parallel orientation, and posterior acoustic enhancement which are the characteristics of benign breast masses [27, 28]. Indeed, many TNBC tumors may be misinterpreted as benign breast tumors due to their benign-like sonographic appearances [19]. Thus, TNBC tumors with high-sTILs level are more likely to be misinterpreted as benign breast tumors, such as fibroadenomas. The breast tumor microenvironment drives the appearance of the tumor and then shapes the tumor. Therefore, the underlying molecular and biological mechanisms of the association between a tumor shape and its surrounding stroma remain to be elucidated.

In addition, the results of our study showed TNBC tumors with high-sTILs were associated with NST invasive carcinoma, histologic grade of 3, ≥ 14% Ki-67 proliferation rate, and inversely associated with associated DCIS component. Despite using different molecular subtypes of breast cancer, the present study and Lee et al.’s study both revealed that high-sTILs level was associated with histologic grade of 3, ≥ 14% Ki-67 proliferation rate, and inversely associated with associated DCIS component [24]. Previous studies have shown that malignant-like sonographic appearances, such as irregular shape, not parallel orientation, and posterior shadowing, are characteristics of low-grade breast cancers with slow cellular proliferation [29,30,31,32]. In contrast, a regular shape or posterior enhancement, typically considered benign breast tumor traits, is associated with high-grade breast cancers with rapid cellular proliferation [30, 31, 33]. Li et al. found that higher histologic grade and higher Ki67 proliferation rate had more chance of having a regular shape of TNBC [19]. In this study, we confirmed that high-sTILs level was associated with higher histologic grade, higher Ki67 proliferation rate, regular shape, and posterior enhancement in the patients with TNBC.

The findings of our study have clinical implications. Many studies demonstrated that high-sTILs level was associated with improved recurrence-free survival, disease-free survival, overall survival [11,12,13], and higher rates of pathologic complete response in the neoadjuvant treatment of TNBC [6, 34]. In addition, Park et al. revealed that stage I TNBC patients with high-sTILs level had a favorable prognosis even without chemotherapy [35]. If sonographic appearance can help identify sTILs level before treatment, then there is the potential for de-escalating therapy for TNBC patients. One crucial benefit of de-escalation is that it avoids the potential toxicity of chemotherapy. Due to allowing for visualization of the entire tumor, ultrasound could overcome the shortcoming of quantifying sTILs level from a needle biopsy specimen with limited tissue sampling and heterogeneity in lymphocyte distribution [17]. Our study is the first to confirm the significant associations between sonographic characteristics and sTILs level by determining sTILs from surgical resection specimens in TNBC patients. Although sonographic characteristics alone cannot replace the pathological evaluation from biopsy, ultrasound may serve as an inexpensive and complementary imaging method for assessing sTILs level, which may provide a predictive and prognostic signature that can be applied to stratify the patients of TNBC to choose the most appropriate treatment.

Some limitations of our study need to be acknowledged. First, it was a retrospective study involving a single institution. In the future, a multi-center study is required for validation. Second, although sonographic features of the index tumor for each patient were retrospectively evaluated by two observers, retrospective evaluation may miss some information or misinterpret the stored ultrasound images. A prospective study should be performed using a video loop stored for sonographic evaluation. Third, since all subjects included in our study were TNBC patients, our study’s findings could not apply to the other different molecular subtypes of breast cancer. Lastly, sTILs constitute a diverse mixture of T cells [36]. A greater CD8+ T cells infiltration is associated with a better prognosis in TNBC [8, 37], while a greater Treg T cells infiltration is associated with a poor prognosis [38, 39]. The evaluation of sTILs would be more complete in case of a further immunohistochemical analysis about the components of the sTILs, dividing them in to two groups: (a) helping tumor suppression like CD8+ T cells and (b) helping tumor progression like Treg (Foxp3+) T cells [39].

Conclusion

In summary, this study investigated the associations of clinicopathologic and sonographic features with sTILs level in TNBC patients. Compared with the TNBC tumors with low-sTILs level, the TNBC tumors with high-sTILs level were more likely to be NST invasive carcinoma, higher histologic grade, higher Ki-67 proliferation rate, and lower frequency of associated DCIS component. In addition, the TNBC tumors with high-sTILs level were more likely to be an oval or round shape, parallel orientation, circumscribed or microlobulated margins, complex cystic and solid echo patterns, posterior enhancement, and less likely to have a heterogeneous pattern and no posterior features. This preliminary study showed that preoperative sonographic characteristics could be helpful in distinguishing high-sTILs from low-sTILs level in TNBC patients.

Data availability

Raw data are available with the corresponding author and will be provided upon a written request.

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Acknowledgements

The authors would like to thank all colleagues for helping us in this study.

Funding

This work was supported by the Zhejiang medicine and health science and technology project (2024KY1402).

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Authors and Affiliations

  1. Department of Ultrasound in Medicine, Hangzhou Women’s Hospital, Hangzhou, Zhejiang, China

    Ling Hu & Yunxia Gu

  2. Department of Ultrasound in Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Ling Hu & Wen Xu

  3. Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Chao Wang

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  1. Ling Hu
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  3. Wen Xu
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Contributions

Study concept and design (LH, CW), acquisition of data (LH, YG, WX), analysis and interpretation of data (LH, YG), drafting of the manuscript (LH), critical revision of the manuscript for important intellectual content (CW), and study supervision (CW). All authors have made a significant contribution to this study and have approved the final manuscript. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Chao Wang.

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Ethics approval and consent to participate

The Institutional Review Board (IRB) of the Second Affiliated Hospital of Zhejiang University School of Medicine (2023 − 0300), and written informed consent was waived. This study was completed in accordance with the Declaration of Helsinki as revised in 2013.

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Not applicable.

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The authors declare no competing interests.

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Hu, L., Gu, Y., Xu, W. et al. Association of clinicopathologic and sonographic features with stromal tumor-infiltrating lymphocytes in triple-negative breast cancer. BMC Cancer 24, 997 (2024). https://doi.org/10.1186/s12885-024-12778-6

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  • DOI: https://doi.org/10.1186/s12885-024-12778-6

Keywords

BMC Cancer

ISSN: 1471-2407

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