We read with interest the work of Janni et al.,1 in which they reported that the presence of cytokeratin (CK)-positive cells in the bone marrow (BM) from patients with breast carcinoma was associated with a very bad prognosis. We believe that their results and conclusions must be interpreted with caution.
First, breast carcinoma cells that metastasize in the BM have a low proliferation rate, with low or no expression of proliferation markers, such as Ki-67 and p120. These observations suggest a limited capacity of chemotherapy to purge breast carcinoma in vivo, in contrast with its capacity to cytoreduce an extramedullary disease; thus, exploring alternative approaches, such as immune-based therapies, could be carried out.
Second, the specificity of A45-B/B3 immunostaining needs to be evaluated carefully. In our experience, we found that 6 of 30 patients (20%) had A45-B/B3-positive cells with unlikely tumor features, which were positive for immunoglobulin G1 control. This kind of false-positive staining may be the result of immunoglobulin subunits reacting with the alkaline phosphatase-antialkaline phosphatase fucsin substrate, as described in mature plasma cells. In addition, BM cells identified by pathologists as plasmocytes, megacaryocytes, and osteoclastic cells may express CKs. These observations are in agreement with the finding of rare A45-B/B3-positive cells in the BM from 7 of 20 patients (35%) in a control group.2 Therefore, as we also found in our experiments, false-positive immunostaining of hematopoietic cells and CK-expressing BM cells may interfere with the immunohistochemical detection of micrometastatic cells in the patient's BM.
Third, several independent studies have shown that the presence of isolated tumor cells (ITC) in the BM at the time of surgery is a strong predictor of early systemic recurrence in patients with positive lymph node status, whereas the reported results from ITC analysis of patients with negative lymph node status have been contradictory. Finally, many CK-positive cells in BM are apoptotic and, thus, are incapable of seeding in metastatic sites. This feature also may explain why many patients with micrometastases in their BM never develop metastatic disease.