Sentinel lymph nodes (SLN) immediately surround breast tumors. The invasion of cancer cells into the SLN is an early sign of metastasis. Being able to predict such an invasion would assist clinicians in making better treatment decisions for individual patients.

Eom et al1 investigated the relationship between SLN metastasis and the expression of carbonic anhydrase IX (CAIX) and XII (CAXII) in patients with early stage breast cancer. CAIX and CAXII are both induced by hypoxia, a low oxygen state that drives malignancy. CAIX is a therapeutic target for cancer, although its exact role has yet to be determined.2 CAXII is a positive prognostic factor in breast cancer. As part of this study, the researchers aimed to identify any clinical or pathological features associated with SLN metastasis.

Researchers retroactively identified patients with early breast cancer who were treated at their institute. They selected a total of 314 patients who had pathological specimens available for immunohistochemistry as well as an SLN biopsy. They also collected detailed clinical characteristics for each patient.

The team used immunohistochemistry to analyze tumor tissue microarrays for both CAIX and CAXII staining. If it was not performed at the time of diagnosis, the researchers evaluated standard biomarkers by immunohistochemistry. These include the estrogen receptor, the progesterone receptor, human epidermal growth factor receptor 2 and Ki-67, a surrogate marker for tumor proliferation.

Of the 314 cases examined, 191 (60.8%) showed CAIX expression in tumor cells. Immunohistochemical staining demonstrated CAIX expression in both the tumor cell membrane and the stromal cells (which surround connective tissue). CAIX expression was strong in areas of intratumoral necrosis.  CAXII was expressed in both the tumor cell membrane and the cytoplasm, but less so in the stromal cells.

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The research team correlated CAIX and CAXII expression with clinical and pathological features as well as patient outcomes. Using univariate, multivariate and risk score modeling, they identified the three most significant risk factors for SLN metastasis:

  • Lymphatic invasion of primary tumors
  • Low Ki-67 labeling index of primary tumors
  • CAIX staining of stromal cells

The identification of lymphatic invasion of the tumor and CAIX-positive stromal cells as risk factors is a novel finding. However, the association between a low Ki-67 labelling index and SLN metastasis is puzzling, given that previous research has shown high levels of Ki-67 to be correlated with tumor proliferation. In the 33 patients lacking all three risk factors, SLN metastasis was absent. CAXII expression was not a risk factor in SLN metastasis.

This study identifies lymphatic invasion, Ki-67 labelling index and CAIX positive stromal cells as potential predictive indicators for SLN invasion and thus potentially for metastasis. We look forward to prospective validation of these indicators and further research into CAIX’s role in early breast cancer.

  1. Eom KY, Jang MH, Park, SO et al. The Expression of Carbonic Anhydrase (CA) IX/ XII and Lymph Node Metastasis in Early Breast Cancer. Cancer Res Treat. 2015 Mar 3. doi: 10.4143/crt.2014.243.
  2. Ivanova L, Zandberga, E, Silina, K et al. Prognostic relevance of carbonic anhydrase IX expression is distinct in various subtypes of breast cancer and its silencing suppresses self-renewal capacity of breast cancer cells. Cancer Chemother Pharmacol.2015 Feb;75(2):235-46. doi: 10.1007/s00280-014-2635-1.