Role of MRI in Breast Cancer Staging: A Case-Based Review

Breast cancer is the most commonly diagnosed cancer in women in the United States and is also the second leading cause of cancer deaths in women. The five-year survival rate and overall prognosis are largely dependent on the stage at diagnosis. Our article highlights the role of magnetic resonance imaging (MRI) in breast cancer staging and updates to the American Joint Committee on Cancer (AJCC) 8th edition guidelines regarding breast cancer staging that are relevant to radiologists. It provides a case-based approach to emphasize the key findings that the radiologist should report on a breast MRI to aid the clinicians in staging and management.


Introduction
Breast cancer is the second most commonly diagnosed cancer worldwide, and the incidence is higher in more industrialized countries. It is the most diagnosed cancer in women in the United States and is the second leading cause of cancer deaths in women. Approximately 250,000 new breast cancer cases were reported in 2016. Both the five-year survival rate and overall prognosis are dependent on staging.
The clinician determines the pre-operative stage of breast cancer by combining the physical examination and radiographic findings. Radiologists should be familiar with the tumor, node, and metastasis (TNM) staging system so that they can convey the most pertinent findings to the clinician. This article discusses the TNM staging system and reviews the role of MRI in accurate breast cancer staging. Although contrastenhanced breast MRI is not a replacement for mammography and ultrasound, it is an important modality in staging breast cancer [1]. MRI better defines the tumor extent, local spread to the skin and nipple, and nodal involvement. It can identify additional tumor sites in 15-27% of patients in the same breast and 3-10% of patients in the contralateral breast [2,3]. This article aims to highlight the usefulness of MRI in breast cancer staging as well as to briefly discuss its limitations.

Breast cancer staging
The American Joint Committee on Cancer (AJCC) is one of the major bodies governing the guidelines for cancer staging. For this study, we used the 8th and latest edition for breast cancer staging that became effective in the United States as of January 1, 2018 (Tables [1][2][3][4][5]. This version incorporates the use of biomarkers in countries where they are widely available to designate prognostic staging. Radiologists should be aware that this will not affect anatomic TNM staging [5][6][7]. Inclusion of biomarkers: tumor grade, hormone receptors, and HER2 (in countries where these are widely available). Inclusion of multi-gene panels. The clinical prognostic stage is assigned regardless of the type of therapy received. Pathologic prognostic stage will be assigned to patients who underwent surgery as initial treatment (excludes patients who received neoadjuvant therapy)

M0
No clinical or radiographic evidence of distant metastasis -cM0( i+) No clinical or radiographic evidence of distant metastasis, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow, or other non-regional nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastasis cM1 Distant detectable metastasis as determined by classic clinical and radiographic means or histologically proven to be larger than 0.2 mm

Key parameters of MRI used in breast cancer staging
The key parameters of MRI used in breast cancer staging and highlighted in our article are described below.

Tumor Size
The primary tumor is usually measured in three orthogonal dimensions, with the largest dimension used for staging purposes. If there is more than one malignant mass in the same breast, the size of the largest tumor should be used for staging purposes [1].

Multifocal and Multicentric Disease
Breast cancers are defined as multifocal when there is more than one distinct tumor within the same quadrant of the breast and multicentric when multiple cancers develop in different quadrants of the breast [8].

Pectoral Muscle Involvement
Pectoralis muscle involvement may be seen as muscle enhancement with obliteration of the fat plane between the tumor and muscle on MRI. However, obliteration of the fat plane as an isolated finding without associated muscle enhancement on MRI does not necessarily indicate muscle involvement [1].

Chest Wall Involvement
Contrast-enhanced breast MRI is the best imaging modality for determining the involvement of the chest wall. Direct invasion and involvement of the ribs, serratus anterior muscle, or intercostal muscles are considered chest wall involvement. According to the TNM staging system of the AJCC, involvement of the pectoralis major or minor muscle alone is not considered chest wall involvement [1].

Nodal Stage
Axillary lymph nodes are divided into levels I, II, and III. The level is based on the relationship between the lymph node and the pectoralis minor muscle. Level I lymph nodes are inferior to the inferolateral border of the pectoralis minor muscle, level II lymph nodes are posterior to and between the lateral and medial borders of the pectoralis minor muscle, and level III lymph nodes are medial to the superior border of the pectoralis minor muscle (including infraclavicular nodes) [1].

Results
The representative cases compiled from our chart review are used to present a pictorial summary emphasizing the role of MRI in breast cancer staging. We have used the recognized descriptors from the American College of Radiology (ACR) standardized Breast Imaging Reporting and Data System (BI-RADS) MRI lexicon, as its consistent use allows for a more uniform descriptive terminology and can be used to dictate subsequent management recommendations [9].

TNM stage: 0 (TisN0M0)
In ductal carcinoma in situ (DCIS), breast MRI can show non-mass enhancement (Tis). The most commonly reported MRI manifestation of DCIS is clumped non-mass enhancement in a ductal, linear, segmental, or regional distribution. Ipsilateral axillary or any other lymphadenopathy (N0) is absent [10]. There will also be an absence of distant metastasis in the MRI field of view (M0). The extent of DCIS of the breast can assist in key surgical planning decisions between lumpectomy and mastectomy ( Figure 1).

FIGURE 1: AJCC TNM stage 0 (TisN0M0)
A 38-year-old premenopausal woman presented with a palpable left breast mass. The diagnostic mammogram was normal. Axial T1-weighted DCE (a), corresponding color-coded map (b), and MIP (c) magnetic resonance images show diffuse non-mass enhancement (red arrows) in the left breast with mixed kinetics. Biopsy depicted DCIS. Findings are consistent with AJCC TNM stage 0 (TisN0M0).

TNM stage: IA (T1N0M0)
In TNM stage IA, in addition to showing a tumor ≤20 mm (T1), MRI will show an absence of axillary lymphadenopathy (N0) and distant metastasis in the field of view (M0). Breast MRI assists with the accurate measurement of tumor size and therefore helps obtain an accurate assessment of T substaging (T1a-c) ( Figure 2).

TNM stage: IB (T0-1N1miM0)
In TNM stage IB, MRI will demonstrate either no tumor or a tumor ≤20 mm (T0-1), without imagingidentifiable lymphadenopathy. However, in stage IB, microscopic metastasis in the ipsilateral axillary lymph nodes (N1mi) is present, which may be discovered during surgery and sentinel lymph node excision. There will also be an absence of distant metastasis in the MRI field of view (M0).

FIGURE 5: AJCC TNM stage IIIA (T3N1M0)
A 40-year-old premenopausal woman presented with a palpable right breast mass. MLO of a screening mammography (a) shows a 6.6 cm irregular mass with indistinct and microlobulated margin (red arrow) in the superior right breast with axillary lymphadenopathy (yellow arrow). Axial T1-weighted DCE subtraction images (b and c) show a 6.6 cm irregular, heterogeneously enhancing mass (red arrow) in the upper outer quadrant of the right breast (red arrow) and associated level 1 axillary lymphadenopathy (dotted yellow arrow). Biopsy depicted invasive ductal carcinoma. Findings are consistent with AJCC TNM stage IIIA (T3N1M0).

TNM stage: IIIB (T4N0-2M0)
In TNM stage IIIB, MRI can demonstrate a tumor with direct extension to the chest wall and/or skin (T4). Skin changes include ulceration and/or edema and/or satellite skin nodules. Lymphadenopathy can be absent (N0), or there can be movable ipsilateral level 1/2 axillary lymphadenopathy (N1), or ipsilateral matted level 1/2 axillary lymphadenopathy, or ipsilateral internal mammary nodes in the absence of axillary lymphadenopathy (N2). There will be an absence of distant metastasis in the MRI field of view (M0) ( Figure  6).

FIGURE 6: AJCC TNM stage IIIB (T4bN1M0)
A 42-year-old female presented with a right breast mass, which on evaluation with a diagnostic mammogram, ultrasound, and subsequent biopsy was proven to be invasive ductal carcinoma. Axial postcontrast T1-weighted MR image (a) exhibits a 6.7 x 6 x 5.9 cm mass (red arrow) with heterogeneous enhancement in the lateral right breast with overlying thick and enhancing skin (dotted orange arrow), concerning for skin involvement (T4). Axial postcontrast T1-weighted subtraction MR image (b) shows a 2.2 x 1.9 x 1.7 cm enhancing mass (green arrow) at the anterior and inferior aspect of the index lesion at 9:00, 6 cm from the nipple. Axial postcontrast T1-weighted subtraction MR image (c) shows right axillary (dotted yellow arrow) and right sub-pectoral lymphadenopathy (blue arrow) (N1). Findings are consistent with AJCC TNM stage IIIB (T4bN1M0).

TNM stage: IIIC (anyT0-4N3M0)
In TNM stage IIIC, MRI can demonstrate no tumor or tumor of any size, even those with direct extension to the chest wall and/or skin (T0-4). It can demonstrate either metastasis in ipsilateral infraclavicular lymph nodes with or without level 1/2 axillary lymph nodes involvement, or ipsilateral internal mammary with ipsilateral level 1/2 axillary lymph nodes, or ipsilateral supraclavicular lymph nodes with or without axillary or internal mammary lymph node involvement (N3). There will be an absence of distant metastasis in the MRI field of view (M0). TNM stage IIIC includes tumors of any T staging. MRI is able to optimally depict the extent of the tumor and even advanced T staging, for example, breast enlargement, diffuse skin thickening, and edema (Figures 7, 8).

TNM stage: IV (anyT0-4anyN0-3M1)
In TNM stage IV, MRI can demonstrate any tumor (T0-4) and nodal (N0-3) staging; however, the key feature is distant metastasis (M1). Breast MRI may be able to identify some cases with distant metastasis, especially to the lung, bones, and occasionally the liver (Figure 9).

FIGURE 9: AJCC TNM Stage IV (T4cN1M1)
A 46-year-old premenopausal woman presented to the emergency room with skin rash, swelling, and suspected abscess of the right breast. Axial T1-weighted subtraction DCE image (a) and corresponding color-coded map (b) show a 10.5 cm round, heterogeneously enhancing mass (red arrows) in the right breast with mixed kinetics. Evidence of diffuse skin thickening and enhancement (short blue arrow) is also noted. Axial T1-weighted subtraction DCE image (c) shows level 1 right axillary lymphadenopathy (dotted yellow arrow). Axial postcontrast T1-weighted image (d) shows diffuse right breast skin thickening (short blue arrows) and the mass (red arrow) abutting the pectoralis major muscle with obliteration of the fat plane and enhancement of the muscle (green circle). Axial PET/CT image shows bilateral FDG-avid pulmonary metastasis (orange circles). Biopsy depicted invasive carcinoma. Findings are consistent with AJCC TNM stage IV (T4cN1M1).

Key information to provide in the breast MRI report
Reporting a breast MRI for breast cancer evaluation should start with understanding the precise clinical question. A detailed description of imaging findings should follow using the recognized BI-RADS descriptors. The findings should be based on the TNM staging, keeping in mind the key findings that will alter treatment as listed below (Tables 6-8). Finally, a concise impression with a final assessment score and a clear recommendation for management will complete the MRI report [1,11,12].

Regional lymph nodes: ipsilateral axillary, internal mammary, and supraclavicular
Axillary lymph nodes are divided into levels using pectoralis minor muscle as a reference

Advantages of using breast MRI for staging
Breast MRI plays an important role in breast cancer screening and diagnosis, based on the current indications, as per the ACR practice parameters [7]. It has traditionally been used as an adjunct modality for the evaluation of complex breast cancer cases or for providing answers to clinical problems when they are not apparent on initial imaging with mammogram and ultrasound. However, primarily because of its excellent ability to define the extent of disease, breast MRI is increasingly proving to be the key noninvasive tool for staging breast cancer, determining treatment options, and preparing for the most optimal surgery [13].
Contrast-enhanced breast MRI has demonstrated utility in identifying additional tumor foci and the extent of disease in patients with known breast cancer. This is especially useful with invasive lobular carcinoma, which is difficult to evaluate on mammography. If neoadjuvant chemotherapy is being considered for breast cancer treatment, a pre-chemotherapy MRI permits the identification of disease extent and allows for more accurate post-treatment evaluation [14].
The best non-invasive tool for assessing accurate tumor size is breast MRI. Tumor size can be underestimated by mammography and ultrasound, but the size of the tumor at histology is not significantly different from that on MRI [15]. In breast MRI, both breasts are imaged at the same time, which helps evaluate contralateral disease. It also assesses for multifocal or multicentric disease, which does alter surgical management [16]. Generally, for multifocal disease (i.e., disease occupying the equivalent of one quadrant of the breast or less), breast conservation surgery can be attempted. On the other hand, for cases of multicentric disease (i.e., disease occupying the equivalent of more than one quadrant of the breast), mastectomy is often required [17]. Contrast-enhanced MRI also allows for simultaneous assessment of the involvement of the pectoral muscle and chest wall. Pectoral muscle involvement does not affect staging but alters surgical management, whereas chest wall involvement affects both. Breast MRI allows for the evaluation of levels 1, 2, and 3 axillary and internal mammary lymph nodes, which not only affects staging and treatment planning but is also the most important deterministic factor for the prognosis of breast cancer. Finally, it is imperative to look for and report extra-mammary findings in the lungs, bones, and visualized liver, especially if they are concerning for distant metastasis [12].

Limitations of breast MRI
MRI is an expensive test and also takes longer to perform than other breast imaging modalities. MRI is contraindicated in patients with non-MRI-compatible cardiac pacemakers, neurostimulators, and certain aneurysm clips, and prosthetic cardiac valves.
MRI is a highly sensitive and specific modality for breast cancer; however, it has its own limitations. The routine use of MRI in pre-operative breast cancer staging is debated, because it has not been shown to improve patient outcomes, including recurrence or mortality. Image-guided biopsy is required to prove multifocal, multicentric, or contralateral cancer when additional suspicious findings are picked up on MRI in a patient with breast cancer.

Conclusions
Radiologists should be familiar with the latest 8th edition of the AJCC TNM staging system for breast cancer. Mammogram, ultrasound, and MRI are all important imaging modalities with specific roles in the evaluation and staging of breast cancer. By applying knowledge of the staging and imaging findings to individual cases, radiologists can play a pivotal role in the decision-making process, alongside breast surgeons and oncologists.
Breast MRI has been used traditionally as a problem-solving tool in breast cancer treatment planning. However, the use of breast MRI as a breast cancer staging tool can provide key information that is critical to both patient management and prognosis.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board University of Florida issued approval IRB202101576. You have received IRB approval to conduct the above-listed research project. Approval of this project was granted on 8/12/2021 by IRB-01. Approved as Exempt. This study is approved as exempt because it poses minimal risk and is approved under the following exempt category/categories: (4)(iii) Secondary research for which consent is not required: secondary research uses of identifiable private information or identifiable biospecimens, if at least one of the following criteria is met: (iii) the research involves only information collection and analysis involving the investigator's use of identifiable health information when that use is regulated under 45 CFR parts 160 and 164, subparts A and E, for the purposes of "health care operations" or "research" as those terms are defined at 45 CFR 164.501 or for "public health activities and purposes" as described under 45 CFR 164.512(b). Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

Conflicts of interest:
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