CA15-3 is associated with breast cancer stage and disease status [2]. Elevated CA15-3 levels are rare in early breast cancer, occurring in less than 10% of stage I cases [1, 3]. Furthermore, elevated CA15-3 levels are extremely rare in patients with DCIS. In Japan, one case of DCIS with elevated tumor markers, CA15-3, NCC-ST439, and BCA255 [4], one case with elevated CA15-3 and NCC-ST439 [5], and two cases with elevated CEA levels [6, 7] have been previously reported. Extensive intraductal involvement was a common feature between these reports and the present case (Table 1). We considered the mechanisms by which CA15-3 is elevated in DCIS.

First, CA15-3 is expressed only on the luminal surface of normal breast tissue. However, in chronic inflammatory conditions, CA15-3 loses polarity and is expressed throughout the plasma membrane [8]. Meanwhile, in breast cancer cells, it is also expressed in the cytoplasm [9]. Mommers et al. reported that 22% of highly differentiated DCIS and 46% of poorly differentiated DCIS also showed CA15-3 expression on the basement membrane side [9].

In the present case, CA15-3 was also positive in the plasma membrane and cytoplasm of the breast cancer cells, leading to a change in polarity. To elucidate the mechanism of CA15-3 elevation, we retrospectively performed an additional immunohistochemical evaluation of tissues at initial presentation and during follow-up (Fig. 5). The results showed a high CA15-3 expression at the initial examination. However, at the second needle biopsy, when tumor markers had decreased, CA15-3 expression had decreased, and normal polarity was observed. Retrospective immunostaining showed that serum CA15-3 was altered along with changes in CA15-3 polarity. The tissue exhibited high levels of CA15-3 expression, but elevated CA15-3 expression alone is not a conclusive diagnostic indicator of cancer. Biopsies were performed at different sites and times because malignancy was suspected, but no malignant findings were confirmed. This case, while uncommon, was diagnosed as a benign disease associated with elevated levels of CA15-3 and was subject to regular follow-up. In addition to testing for CA15-3, we also evaluated the expression of CEA in specimens from the first and second needle biopsies; CEA was localized to the luminal surface in both biopsies (Fig. 5). Although the levels of CA15-3 and CEA in serum showed similar trends, there is no satisfactory explanation for the differences in the expression patterns of the two markers between these tissues. However, it is suggested that this may be due to tumor heterogeneity.

Expression of CA15-3 and CEA in core needle biopsy. a Expression of CA15-3 and b CEA in the first biopsy. CA15-3 was strongly positive throughout the mammary gland cells, and CEA was expressed only on the luminal surface. c Expression of CA15-3 and d CEA in the second biopsy. After the tumor markers had spontaneously decreased, CA15-3 was expressed on the luminal surface

Second, inflammation of the breast tissue has also been implicated. In this case, pain and redness of the breast were observed at the time of the initial examination, and histological biopsy showed infiltration of stromal inflammatory cells. In addition, fat-suppressed T2-weighted breast MRI showed high signal intensity in the dorsal side of the mammary gland, a finding that reflects lymphocytic infiltration, vasodilation, and increased vascular permeability [10, 11].

The clinical course of the patient showed improved subjective symptoms and a decrease in CA15-3 levels, with a decrease in high signal intensity on fat-suppressed T2-weighted MRI. However, preoperative examination showed increased high signal intensity in the dorsal side of the mammary gland and re-elevation of CA15-3. These findings suggested that inflammation of breast tissue may be involved in the migration of CA15-3 into the blood. However, treatment with antibiotics and steroids was unsuccessful, and the cause of inflammation remains unknown. This needs to be investigated in future case series.

In addition, there were no reports of elevated CA15-3 levels in lymphoma, although classical Hodgkin lymphoma was observed incidentally. Further, the fact that tumor markers improved in the early postoperative period and before the treatment for lymphoma led us to conclude that the cause of the elevated CA15-3 level was DCIS. In this case, inflammatory breast cancer was suspected at the initial diagnosis, but no malignant findings were found on the biopsy. Increased CA15-3 expression in peripheral blood may also be observed in carcinomas other than breast cancer, benign breast tumors, ovarian cancer, endometriosis, and ovarian cysts [12, 13]. In the present case, a systemic examination was performed after suspicion of other diseases, but no other lesions were found, and the patient was diagnosed with mastitis.

Follow-up with a diagnosis of chronic mastitis with an elevated CA15-3 level and continued frequent follow-up led us to the diagnosis of DCIS and early treatment. Our experience with this case suggests that immunohistochemical staining of tissue is useful to identify the lesion responsible for the elevated tumor marker, even in benign lesions. Further, it is important to continue regular surveillance of benign lesions with elevated tumor markers.