Tracing Magtrace ® Under Microscope in Breast Tissue and Sentinel Lymph Nodes

Magtrace^® is a commercial name for superparamagnetic iron oxide (SPIO) nanoparticles, used for axillary sentinel lymph node (SLN) detection in breast cancer. The SPIO tracer method, also known as the magnetic technique, is non-inferior to radioisotope and blue dye for axillary SLN detection. ¹ The SPIO technique also provides the added benefit of scheduling flexibility, allowing the tracer to be injected days, weeks, or months before surgery or right before the procedure. ² The SPIO technique allows late lymph node removal, since the tracer can be detected in the SLN, with a detection window that extends beyond 30 days. This advantage is beneficial for breast surgeries performed for ductal carcinoma in situ (DCIS) and prophylaxis, where upfront SLN biopsies may not be indicated, but later required when invasive disease is found.

Although SPIO has been used clinically since 2018, its microscopic appearance is not well documented in the published literature. ³ Our literature search yielded limited reports on histological description of SPIO in breast parenchyma and lymph nodes.^1–4 Our breast surgical team recently started using SPIO, in combination with radioisotope and/or blue dye for axillary SLN detection. With this brief report, our goal is to increase breast pathologists’ awareness of the histological appearance of SPIO; histological identification of SPIO is essential for clinical-histological correlation, accurate histological diagnosis, and avoiding unnecessary histological workup. We present brief clinical features and SPIO-related histological findings in breast and lymph node tissue of 3 breast cancer patients who underwent Magtrace^® SLN biopsies.

Patient 1: A 48-year-old female patient underwent right partial mastectomy for 12 mm ER-positive DCIS. Three SLN and one palpable lymph node were removed. Magtrace^® and radioactive tracer were used for SLN detection. The brown pigment in all 3 lymph nodes was attributed to dermatopathic lymphadenopathy in the final diagnosis. Patient 2: A 50-year-old female patient with a pathogenic CHEK2 germline mutation underwent right skin-sparing mastectomy with SLN biopsy with Magtrace^® for multifocal invasive ductal carcinoma. One of the 7 SLNs showed macrometastasis, and 2 lymph nodes showed isolated tumor cells. All 7 lymph nodes and the subareolar breast parenchyma showed brown-colored Magtrace^®. Patient 3: A 42-year-old female patient underwent neoadjuvant chemotherapy, followed by nipple sparing mastectomy and targeted axillary dissection for a node-positive (pre-therapy) ER-/HER2+ invasive ductal carcinoma. The SLN was identified with methylene blue and Magtrace^®. Breast tissue showed a pathologic complete response. One SLN showed therapy-related changes and Magtrace^® deposits.

Across all specimens, Magtrace^® (SPIO) demonstrated a consistent microscopic appearance. On low-power examination, in breast parenchyma (patient # 2; Figure 1A), the tracer material appeared as diffuse golden-yellow to brown discoloration of the subareolar fibrous connective tissue. Dark brown, dense, angulated material was present in the dermal lymphatics (Figure 1C). As far as we know, this is the first histological description of the SPIO in the subareolar dermis and breast parenchyma. In lymph nodes, Magtrace^® was present as a diffuse golden-yellow discoloration of the subcapsular and medullary sinuses (Figure 1D). Chunky, dense, dark brown deposits were present within the perinodal lymphatics (Figure 2A). Previous report identified SPIO deposits mostly intracellularly in the macrophages in the lymph node sinuses. ³ We noted SPIO deposits inside macrophages, as well as extracellular material in the lymph node sinus, subcapsular sinus and perinodal lymphatics. Prussian blue stain highlighted the iron oxide particles in the lymph node capsular sinuses, medullary sinuses, and fibrous tissue (Figures 1E, 1F & 2B).

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Figure 1.

SPIO material in the subareolar breast tissue (patient # 2, A-C) and sentinel lymph node (patient 1, D-F). The subareolar fibrous connective tissue shows brown discoloration (panels A & B; box). SPIO is present as dense brown material in the dermal lymphatics (C, arrows). In sentinel lymph node, the sinuses show diffuse brown discoloration (panel D). Prussian blue stain highlights the SPIO material blue (panels E & F).

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Figure 2.

SPIO material in the sentinel lymph node (patient # 2, post neoadjuvant therapy). SPIO material is present in the perinodal lymphatics (panel A, arrows) and fibrous tissue. Prussian blue stain highlights the diffuse distribution of SPIO in the lymph node fibrous tissue. SPIO material in the lymphatics stains strongly with Prussian blue stain. (Panel B, arrow).

Usually, the lymph nodes identified with the SPIO tracer are brown-colored; the gross discoloration of the lymph nodes in these 3 specimens could not be confirmed. It has been reported that injection of the tracer into the subareolar region may leave a subtle brown discoloration at the injection site, and this pigmentation can persist on the skin for several years and may occasionally be noted during gross examination. ² Our findings show that the SPIO tracer can be identified microscopically in the breast tissue at the site of injection (subareolar tissue) and in the SLNs. On formalin-fixed, paraffin-embedded tissue sections, with hematoxylin and eosin (H&E) stains, the tracer is seen as a diffuse golden yellow to dark brown discoloration of the fibrous connective tissue in the breast and lymph node sinuses. Tracer is also identified in the lymphatic channels in the breast dermis and perinodal tissue as dark and more chunky deposits. The histological appearance and location of the tracer material in the LN tissue were similar in neoadjuvant therapy and therapy-naive settings.

The differential diagnoses for SPIO tracer include melanin and hemosiderin deposits in the lymph node and orange/yellow ink material in the breast tissue. While the color of SPIO tracer can mimic these deposits, its location and distribution are unique and different. The tracer material is located extracellularly in the histological sections, and its distribution is observed in the breast stromal fibrous tissue only and confined to the lymph node sinuses. Dense chunky golden-brown deposits in the lymphatics are also commonly observed, which is not a feature of melanin, hemosiderin or ink deposits. Hemosiderin is golden brown or rust-colored pigment, typically appearing as coarse, refractile cytoplasmic granules within macrophages. Melanin is fine, granular yellowish brown to dark brown or black in H&E staining. In dermatopathic lymphadenopathy, melanin pigment is often identified inside the macrophages in the paracortical region. On H&E, hemosiderin pigment, as compared to melanin, is more clumped and refractile, and more heterogeneous in size and color density. Prussian blue stains hemosiderin blue to black color, while Fontana-Masson stains melanin black. Prussian blue stain does not color yellow-orange ink. Therefore, SPIO tracer can be highlighted with Prussian blue stain if differentiation on H&E is difficult. ⁵

In conclusion, SPIO tracer-related histological findings are seen in the breast as well lymph node and perinodal tissue. A knowledge of SPIO tracer-related histological artifacts can avoid unnecessary histological workup.