Mammographic microcalcifications and breast cancer tumorigenesis: a radiologic-pathologic analysis

Mammographic MCs serve as important diagnostic markers of benign and malignant breast lesions. However, there is still a lack of consensus regarding the genesis of MCs and their relationship with breast cancer pathology. Our study indicates that presence of both malignant and benign mammographic MCs is associated with poor prognostic factors of breast cancer, and could serve as indicators of aggressive tumor growth.

This study found a positive relationship between the presence of MCs and over-expression of HER-2. HER-2 is a valuable therapeutic and prognostic marker in primary breast carcinomas [10]. It plays a significant role in the HER family of receptors, normally involved in regulating breast growth and development. Over-expression of HER-2 proto-oncogene, called c-erbB-2, is associated with breast cancer [11]. This gene is amplified in approximately 20 to 30% of breast cancers and is associated with aggressive tumor behaviour [12]. Wang et al. [10] conducted a retrospective study of 152 patients, and found MCs were more common in carcinomas with HER-2 over-expression at a prevalence of 61.6% compared to those without HER-2 at 35.4%. Similarly, Seo et al. [13] also found an association between mammographic MCs and HER-2 over-expression in 498 patients. Our study further confirms a greater prevalence of MCs (52.9%) among tumors over-expressing HER-2, compared to tumors without HER-2 amplification (33.8%). This is further reinforced by the figures, showing presence of MCs for a HER-2 positive patient (Figure 1) and a complete absence of MCs for a HER-2 negative patient (Figure 2). However, unlike Seo et al. [13] who found more MCs in patients with HER-2 over-expression under the age of 50, our results showed that the presence of MCs was independent of patient age (p = 0.100). Our study cohort was also twice (n = 937) as large as the population assessed by Seo et al. (n = 498). Given the strong association, MCs could serve as early indicators of HER-2 over-expression, warranting further molecular investigation into their relationship.

Hormone receptor status is useful for its prognostic significance and treatment planning in patients with advanced breast cancer. Previous studies have investigated the association between MCs and hormone receptor status with variable results. Griniatsos et al. [14] found an increased number of patients with both estrogen and progesterone receptor positive tumors presented with mammographic MCs. Similarly, Karamouzis et al. [15] also found MCs in over 65% of ER positive, and over 46% of PR positive tumors. On the contrary, Ferranti et al. [16] found an inverse relationship between mammographic MCs and hormone receptor positive lesions. The prognostic significance of ER and PR expression has been a matter of debate for many years. However, current available evidence suggests that ER/PR negative tumors have a worse prognosis altogether [17]. Similar to Gajdos et al. [18], our study showed that the presentation of MCs is independent of hormone receptor status.

Furthermore, strong correlations between MCs and tumor grade, tumor histology, and breast density highlight the prognostic significance of these calcium deposits. Our results showed that a higher prevalence of MCs was found among patients with high grade tumors than those with low grade tumors. This result reinforces previous studies, such as that by Palka et al. [9], which showed a strong relationship between MCs and high grade lesions. Conversely, Dinkel et al. [19] found this correlation to be poor and inconclusive.

To better understand these associations, the relationship between mammographic breast densities was compared to the presence of MCs. The physical composition of the breast varies, with different proportions of fat, connective tissue, ductal and lobular elements contributing to differences in mammographic breast density. The greater the number of fibroglandular tissue, the higher the category of breast density. Our results confirmed those of Skandalis et al. [20], who found elevated levels of MCs in patients with heterogeneously dense breasts and high tumor grades. We found MCs to be significantly associated with heterogeneous breast densities, with a high prevalence of fibroglandular tissue.

The link between tumor grade and breast density highlights some molecular factors giving rise to MCs and contributing to tumorigenesis. Tabar and Dean [21] propose that high-grade ductal carcinomas undergo a process called neoductogenesis, promoting vascular invasion, with excessive lymphatic and hematogenous spread, leading to a worse tumor prognosis. A high prevalence of fibroglandular breast tissue can lead to increased accumulation of versican, a proteoglycan associated with high tumor grade and invasive disease in patients with high breast densities and mammographic MCs [20].

Approximately 90% of ductal carcinoma in situ (DCIS) appear as MCs, 40% of which progress to an invasive breast cancer. Among invasive carcinomas, our study further discovered a greater prevalence of MCs in multifocal invasive disease (47.9%) than unifocal invasive disease (36.1%). Tot et al. [22] studied the influence of tumor focality on breast cancer survival, and found the highest ten year survival rate to be amongst patients with unifocal tumors. Multifocal tumors serve as poor prognostic parameters in breast cancer, and their strong association with MCs further reinforces the role of MCs as poor prognostic indicators of breast cancer.

There was no significant outcome difference between patients with MCs and those without MCs. Recurrence was measured using a 5 year recurrence end-point, and there was no statistical association between having MCs on mammography and recurrence pattern (p = 0.258).

These results could also be affected by our study limitations. Our study population was limited to St. Michael’s hospital, whereas a multi-site analysis would have allowed for a more rigorous analysis. We also conducted a retrospective chart review, where missing data on electronic charts could not be included in the study. Hence, as seen in Table 1, numbers for all variables vary due to incomplete information recorded on patient charts. Inclusion of additional biomarkers, such as p53 and further genetic analysis would have further improved our understanding of the relationship between MCs and breast cancer.

Furthermore, MCs smaller than 130 μm were not visible on our digital mammogram [23]. In these circumstances, histological examination of breast tissue can reveal smaller MCs that were missed in mammography. To test for MCs that were missed in mammograms, we compared the presence of MCs among pathology and mammography reports for each patient. Table 3 further depicts these discrepancies. Our study showed that 52.2% of MCs that were absent on mammograms were visible under a histological examination. Hence, our results were influenced by the size limitations of mammograms. Also, we did not examine the chemical composition of MCs, which would have been useful for an accurate understanding of their role in breast tumorigenesis.