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Abstract

Background

Internal mammary lymph node (IM) metastasis significantly affects prognosis. However, reports using imaging techniques have been limited. Diffusion-weighted imaging with background suppression and maximum intensity projection (DWIBS-MIP) is a sophisticated imaging method that emphasizes key signal areas such as tumors or lymph nodes in three-dimensional, providing a quick and comprehensive view immediately. Therefore, DWIBS-MIP can become a screening method for IM metastasis.

Purpose

To investigates the usefulness of DWIBS-MIP for screening IM metastasis in patients undergoing preoperative breast MRI.

Material and Methods

Breast cancer patients with suspected IM metastasis from January 2017 to June 2024 were assessed. We evaluated the visibility and the size of IM metastasis, the long axis, short axis, and short-to-long axis (S/L) ratio of the biopsied lymph nodes at DWIBS-MIP. Patient’s age, maximum diameter and hormonal status of primary cancer, breast cancer stage, the presence of axillary lymph node (Ax) metastasis, the location of the primary lesion were evaluated.

Results

This study included 31 patients with IM metastasis and eight without IM metastasis. DWIBS-MIP exhibited a predictive value of 79.5% for screening IM metastasis. Between two groups, morphological characteristics of IM lymph nodes, including the long axis, short axis, and S/L ratio, demonstrated no significant differences. A higher proportion of Ax metastasis was possible in cases with IM metastasis. Other clinical data did not indicate significant differences.

Conclusions

DWIBS-MIP provides an easy and effective assessment method for screening IM metastasis. The study indicates incorporating DWIBS-MIP into routine clinical practice can improve IM detection accuracy.

Keywords

breast cancer internal mammary lymph node metastasis diffusion-weighted imaging with background suppression maximum intensity projection

Introduction

Internal mammary lymph nodes (IMs) exist along the internal thoracic veins and arteries, and they present to the same extent on both sides, according to autopsy cases or anatomy textbooks.^1–3 Additionally, IM is depicted as lymph nodes that receive direct perfusion from the breast much less frequently than axillary lymph nodes (Ax) in lymph node scintigraphy conducted during breast cancer surgery.⁴ Therefore, they are considered crucial as sentinel lymph nodes where breast cancer may first metastasize. However, current international standards for breast cancer imaging, including BI-RADS and the NCCN guideline, do not specify diagnostic methods for the internal mammary (IM) lymph nodes.^5,6 Furthermore, they are not routinely removed intraoperatively and are not a routine target for ultrasound (US)-guided biopsy. This is because no imaging screening and diagnostic methods are available that routinely determine IM metastasis and there has been a long-standing controversy regarding pathological diagnosis, including preoperative biopsy.

In recent years, several large-scale studies have revealed that the effect of IM metastasis on prognosis cannot be ignored, comparable to Ax metastasis.^7,8 The tumor, nodes, and metastasis staging in the American Joint Committee on Cancer Staging Manual indicated that the clinical staging is upgraded to N2b or higher, regardless of the presence of Ax metastasis, if IM metastasis is clinically evident through imaging or biopsy.⁹ Studies have demonstrated that 10%–30% of IMs are positive for metastasis when excised during breast cancer surgery, and this percentage increases when all lymph nodes, not just suspicious ones, are excised and biopsied.^1,10 A report investigating IM metastasis that is incidentally excised during rectus abdominis myocutaneous flap reconstruction revealed that none of the IM metastases could be detected by imaging.¹⁰ This may be because imaging techniques for screening IM metastasis remain not established. This indicates that micrometastasis at IM without lymph node enlargement may exist to some extent, comparable to Ax metastasis.

To the best of our knowledge, very few studies directly investigated the visibility and morphology of IM based on pathological results, including surgery or biopsy.^11–14 Additionally, reports investigating the effects of radiation therapy on the IM region in prospective studies do not reference the size or morphology of IM itself.^15–19 Therefore, evaluating the visibility and imaging of IM itself provides valuable information for selecting treatment options aimed at improving disease-free survival and overall survival, particularly by applying radiation therapy to the internal thoracic area.

We focused on diffusion-weighted imaging (DWI) within various imaging modalities. DWI with background suppression and maximum intensity projection (DWIBS-MIP) is a sophisticated imaging method that emphasizes key signal areas with a high cellular density, such as tumors or lymph nodes in three-dimensional (3D), thereby providing a quick and comprehensive view immediately.^20,21 A previous study revealed that it enables a more effective assessment of tumor size changes after neoadjuvant chemotherapy for breast cancer, especially when compared with traditional 3D contrast-enhanced MRI.²² Therefore, DWIBS-MIP can become a screening imaging technique for assessing IM metastasis. This study aims to investigate the usefulness of DWIBS-MIP for screening IM metastasis in patients undergoing preoperative breast MRI.

Materials and methods

Patients

The ethics committee of the institution approved this retrospective study and waived the informed consent. We conducted a full-text search of imaging diagnostic reports in patients undergoing preoperative breast MRI from January 2017 to June 2024, determining female patients with a pathological diagnosis of breast cancer. The inclusion criteria are patients who demonstrated clearly round or oval high-signal intensity in the internal thoracic region at the affected side, indicating IM first on DIWBP-MIP and then confirmed by contrast-enhanced MRI (Ce-MRI) and US and underwent US-guided biopsy. The exclusion criteria were cases with no US-guided biopsy conducted due to patient preferences or because of minimal benefits of the biopsy related to breast cancer stages, cases where Ce-MRI was performed after IM biopsy, cases with strong artifacts near the sternum due to the primary lesion or other factors making internal mammary lymph node diagnosis difficult, cases that underwent radiation therapy in the internal mammary region, and cases with an inadequate specimen. This study included cases after contralateral breast cancer surgery without recurrence for more than 5 years and without radiation therapy. Only the breast cancer on the side where the biopsy was conducted was included for simultaneous bilateral breast cancer. Preoperative MRI of patients extracted by these criteria was investigated. Finally, this study included 39 patients.

At our institution, all patients, including those determined to be negative for IM metastasis on preoperative MRI in this study, undergo follow-up imaging with MRI or ultrasound at intervals of no more than 1 year. The internal mammary region is always assessed during these follow-ups. Patients who were determined to have no metastasis at the time of follow-up were considered negative for recurrence.

MRI technique

All MRI examinations were conducted with a 3.0 T superconductive MRI scanner (Ingenia, Philips Healthcare) with a 16-channel body array coil. Ce-MRI was performed with enhanced T1 high-resolution isotropic volume excitation. The sequence parameters were shortest/shortest repetition/echo time; flip angle of 10°; slice thickness of 1.8 mm; acquisition field of view of 330 × 330 mm; acquisition matrix of 400 × 320; and centric k-space trajectory. Gadobutrol was injected at a rate of 1 mL/s, and the dynamic phases were acquired at 20 s, 85 s, and 5 min after the injection. DWI was conducted with Echo Planer Imaging with the following parameters: acquisition field of view of 330 × 330 mm; acquisition matrix of 128 × 128; b value of 0, 1000; number of excitations of 1 for b-value of 0 and 3–5 for b-value 1000; short tau inversion recovery fat suppression; echo planer imaging factor of 47; repetition/echo time of 6000–10,000/62-80 ms; flip angle of 90°; parallel acquisition technique with reduction factor 2, using the Sensitivity Encoding algorithm; slice thickness of 3 mm; slice gap of gapless; and acquisition time of 6 min. An MIP was established on the MRI console, also known as DWIBS-MIP, for DWIBS images.

MRI image analysis and clinical evaluation

One radiologist, who was unaware of the IM metastasis results, used DWIBS-MIP to determine circular or oval areas demonstrating equal-to-high signal compared to the Ax, indicating IM, and confirmed them using Ce-MRI and US. Subsequently, the radiologist recorded the long axis, short axis, and short axis-to-long axis (S/L) ratio of the biopsied lymph nodes using DWIBS-MIP.

Additionally, we investigated the patient’s age, primary cancer maximum diameter, breast cancer stage, primary cancer hormonal status, and the presence of Ax metastasis. The location of the primary lesion was categorized as being in the outer quadrants or elsewhere.

Pathological evaluation

All biopsies of the IMs were conducted under US guidance using either core needle biopsy or fine needle biopsy. Pathologic assessment of pretreatment biopsy specimens was performed by a pathologist. Estrogen receptors, progesterone hormonal receptors, and human epidermal growth factor receptor type 2 (HER2) expressions were assessed. The luminal subtype was defined as positive estrogen or progesterone expression and negative HER2 expression. The HER2-enriched subtype was considered HER2 overexpression. The triple-negative subtype involved negative hormonal expression and negative HER2 overexpression. Estrogen receptor staining between 1% and 9% was categorized as positive under the St Gallen International Expert Consensus 2015.²³

Statistical evaluation

EZR software (Saitama Medical Center, Jichi Medical University, https://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html), a graphical user interface for R (The R Foundation for Statistical Computing, version 3.6.0), was used for statistical analyses were performed using. A statistical evaluation was conducted for each item between the groups with and without metastasis. Comparisons of age, primary cancer size, short and long axis, and S/L ratio were conducted using the Wilcoxon rank sum test. Contingency tables were established and Pearson’s chi-square test was conducted for the primary cancer location, hormonal status, and presence of Ax metastasis. All data are presented as medians (minimum-maximum). A p-value of <.05 indicated significance for all analyses (Fig. 1).

Figure 1.

Representative case of internal mammary lymph node metastasis on diffusion-weighted imaging with background suppression and maximum intensity projection. Legend: A right breast cancer case with an oval-shaped high-signal intensity on the internal mammary region on DWIBS-MIP (a), confirmed as a true lymph node at contrast-enhanced MRI (b). The size of the lymph node is 9.52 × 4.99 mm on DWIBS-MIP (c).

Results

The study included 31 cases with metastasis and 8 cases without metastasis. Figure 2 presents an overview of the patient selection process, and Table 1 shows the characteristics of the patients and details of the results.

Figure 2.

Study flowchart of patient selection.

Table 1.

Characteristics of the patients and details of the results.

		Metastatic	Non-metastatic
		(n = 31)	(n = 8)	p-value
Age		54 (34–82)	50 (34–68)	.58
Biopsy method	Fine needle aspiration	24	8	.33
	Core needle biopsy	7	0
Primary cancer size		31 (7–94)	31 (24–84)	.49
Primary cancer location	Lateral	9	2	>.99
	Central, medial	22	6
Primary subtype^a	ER/RP+, HER2−	11	2	.12
	ER/PR+, HER2+	5	0
	ER/PR−, HER2+	4	4
	Triple negative	10	2
Stages	IIA	0	3	<.01
	IIB	0	2
	IIIA	7	0
	IIIB	0	1
	IIIC	24	2
Ax metastasis	Positive	28	5	.09
	Negative	3	3
Short axis on DWIBS-MIP (mm)		6.6 (1.1–12.3)	6.7 (4–9.7)	.93
Long axis on DWIBS-MRI (mm)		11 (5.8–17.4)	9.8 (7.8–16.7)	.92
S/L ratio on DWIBS-MIP		1.5 (1–5.4)	1.6 (1.1–2.1)	.83
All data are represented by the median and interquartile range

^a1 case not available in the metastatic group.

S/L: short-axis to long axis; DWIBS: Diffusion-weighted whole-body imaging with background body signal; MIP: maximum intensity projection; ER: estrogen receptors; PR: progesterone receptors; HER2: human epidermal growth factor receptor type 2; Ax: axillary lymph node.

All the IMs that underwent biopsy were visible at DWIBS-MIP, and the positive predictive value for metastasis (PPV) was 79.5% (31/39). Between the group with metastasis and without metastasis, short axis (mm), long axis (mm), and S/L ratio on DWIBS-MIP demonstrated no significant differences: 6.6 (1.1–12.3) and 6.7 (4–9.7), p = .93, 11 (5.8–17.4) and 9.8 (7.8–16.7), p = .92, 1.5 (1–5.4) and 1.6 (1.1–2.1), p = .83, respectively.

No significant differences were observed in primary cancer size, location, and hormonal status. The proportion of Ax metastasis was higher in patients with IM metastasis but with no significance: 28 (90%) out of 31 cases in the group with metastasis and 5 (63%) out of 8 cases in the group without metastasis (p = .09). Among the cases where IM lymph node metastasis was positive, 9.8% (3/31) had negative axillary lymph node metastasis, indicating isolated IM metastasis.

For patients determined to be negative for IM metastasis on preoperative MRI, no recurrence in the internal mammary lymph node region was observed in any patient during the follow-up period.

Discussion

Our study revealed that the diagnostic ability of DWIBS-MIP for IM metastasis exhibited a good PPV of 79.5%. No significant differences in the size of IM on DWIBS-MIP were observed between the groups with and without IM metastasis. The proportion of Ax metastasis was higher in patients with IM metastasis but with no significance. No significant differences were found between the two groups in terms of primary cancer size, location, and hormonal status.

The diagnostic capability, especially the PPV, of DWIBS-MIP for diagnosing IM metastasis was good, and no cases had IM metastasis that DWIBS-MIP could not confirm. This result almost corresponds to previous reports: PPV of 81% (35/43) from Lee et al. and PPV of 77.3% (140/181) from Cho et al.^12,14 Contrarily, the result does not correspond with the previous report: PPV of 25% (18/73) from Kim et al.¹³ To the best of our knowledge, only a few reports investigated IM using DWI. Additionally, the diagnostic criteria for IM in DWI have no consensus. Kim et al. concluded that the presence of diffusion restriction was not useful for predicting IM metastasis, and they did not establish the reference signal value.¹³ The lack of a reference signal to identify IM positivity is also predominant in other studies.^12,14 Therefore, we identified the signal intensity of Ax as a reference.

The apparent diffusion coefficient (ADC) is an important indicator when discussing DWI. Lee et al. revealed that ADC value was significantly lower in cases with IM metastasis. In contrast, Kim et al. demonstrated that ADC value was not useful for diagnosing IM metastasis. However, they did not identify the standard for ADC values.^12,13 Based on these reports, we aimed to measure ADC values in our study. However, setting a region of interest was difficult even in cases where a high signal was confirmed by DWIBS-MIP because the IM is a relatively small structure and the internal thoracic region is relatively prone to artifacts due to distortion. Therefore, we decided not to measure ADC in this study.

The evaluation of IM indicated no significant differences in any of the indicators. To the best of our knowledge, only a few reports have evaluated IM using MRI for predicting IM metastasis.^11–14 All these reports revealed that the size of IM was useful for predicting metastasis, contrary to our results. Our study revealed no significant differences due to the following: a small number of cases; low threshold for criteria requiring lymph node biopsy at our facility, which may cause a high rate of false negatives; measurement by DWI. Regarding the first two points, the number of cases needs to be increased for further investigation. Regarding the use of DWI for measurement, this study did not primarily aim to differentiate between benign and malignant lesions but rather aimed to simplify the screening of metastasis in IM. Recognizing that, at present, a comprehensive assessment combining other modalities, such as Ce-MRI, will be required in the future is important in the differentiation between benign and malignant lesions.

No significant differences were found between the two groups in terms of primary cancer size, location, and hormonal status, or Ax node metastasis. Among these, the only trend observed was in the Ax, with a higher proportion of positive Ax metastasis in cases with IM metastasis. This is similar to previous reports, and numerous studies indicate that the presence of Ax metastasis is significantly higher in cases confirmed to be IM metastasis-positive by biopsy.^{10,13,14,23–25}

From the perspective of IM treatment, radiotherapy is the main treatment, as IMs are not lymph nodes that are routinely removed intraoperatively. Ax metastasis positivity used to be a predominant criterion for adding radiotherapy to the internal mammary region, which has extended disease-free survival and overall survival, is reasonable.^16,17,19,26 However, these studies did not pathologically diagnose IM, which poses a risk of not adding radiotherapy in cases where only IM metastasis is positive without Ax metastasis. A review indicates that breast cancer metastasizes only to IM in 1.2%–17.9% of cases, and our study indicated a similar rate of 9.8% (3/31).²⁷ These figures indicate that deciding to add radiation therapy to the internal thoracic region based on the presence or absence of Ax metastasis may indirectly result in up to 20% of patients with actual IM metastasis not being treated with radiation therapy. The use of DWIBS-MIP for screening IM metastasis is expected to become a criterion for imaging in the adoption of radiotherapy to avoid this risk and further extend disease-free survival and overall survival by adding radiotherapy to the internal mammary region. Therefore, regardless of the presence or absence of Ax metastasis, screening for IM metastasis is essential for the adoption of radiotherapy.

This study has several limitations. First, the study population and number of events were small. However, this is preliminary research conducted to propose the usefulness of DWIBS-MIP for assessing IM metastasis. Second, biopsies have sampling errors. This is particularly likely to occur with micrometastasis. However, unlike Axs, IMs are not lymph nodes that are routinely removed intraoperatively. Therefore, there’s always an issue with confirming the final pathology results of IM metastasis. Hence, there’s a demand for non-invasive imaging evaluation methods, and our results will contribute to this.

In conclusion, DWIBS-MIP is a useful and easy method for screening IM metastasis in breast cancer.

Footnotes

Acknowledgments

The Authors would like to thank Enago () for the English language review.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Taiyo L. Harada

Takayoshi Uematsu

Kazuaki Nakashima

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A preliminary study on diffusion-weighted imaging with background suppression and maximum intensity projection for screening internal mammary lymph node metastasis of breast cancer

Abstract

Background

Purpose

Material and Methods

Results

Conclusions

Keywords

Introduction

Materials and methods

Patients

MRI technique

MRI image analysis and clinical evaluation

Pathological evaluation

Statistical evaluation

Results

Discussion

Footnotes

Acknowledgments

Declaration of conflicting interests

Funding

ORCID iDs

References