Hormone-replacement therapy (HRT) is the most effective intervention to manage estrogen-deficiency symptoms and to reduce the osteoporosis risk in postmenopausal women.
Despite the proven efficacy, the major concern is that the long-term use of HRT has been correlated with an increased risk of breast cancer Citation[1–3]. In the last few years, a growing amount of evidence has demonstrated that the risk of invasive breast cancer is concentrated on tumors with invasive lobular carcinoma (ILC) and invasive ductal–lobular mixed carcinoma (IDLC) histology Citation[4–10]. Since lobular cancers have different biological and clinical features compared with invasive ductal cancers (IDCs), there might be relevant implications for the diagnosis, as well as surgical and medical treatment.
Epidemiology of HRT use & ILC
Epidemiological data have shed light on the association between HRT use and lobular histotype. The analysis of nine cancer registries in the Surveillance, Epidemiology and End Results (SEER) program revealed that the incidence rates of lobular cancers increased remarkably from 1987 to 1999, mainly in postmenopausal women, whereas the incidence of IDC remained stable over the same years Citation[4,9].
This trend has also been confirmed by the analyses of European cancer registries performed in the same period and also in more recent years. In the Geneva cancer registry, ILC incidence from 1976 to 1999 was found to rise 14.4% per year, with the most relevant increase in women aged 50–59 years Citation[11]. The comparison of data from Geneva and The Netherlands cancer registries showed that from 1989 to 2003, the annual increase in ductal cancer incidence was similar in The Netherlands (2.3%) and Geneva (2.5%), whereas the annual increase in lobular cancers was higher in Geneva (10%) compared with The Netherlands (5%). Since both populations fully accomplished mammography (Mx) screening, a reliable explanation for these discrepancies was the higher prevalence of HRT use in Geneva than in The Netherlands Citation[12].
A French prospective, observational, nationwide study performed from 2001 to 2002, reported that in HRT past and present users, ILC and IDLC incidence rates were 14.3 and 4.9%, respectively, compared with 10.7 and 1.9% in women who had never undergone HRT Citation[13].
HRT & ILC
Although long-term HRT use has been associated with an increased breast cancer risk, the impact appears to be different depending on histological type. Several studies have reported that past and current users of combined HRT are at a higher risk of developing ILC than IDC. Furthermore, there seems to be an exposure effect, since in some reports ILC risk was found to increase as the duration of HRT use increased Citation[4–9,14,15]. It is generally accepted that combined HRT preparations affect breast cancer risk more significantly than estrogens alone (estrogen-replacement therapy [ERT]) Citation[1–3,16,17]. Indeed, even long-term use of ERT was not associated with an increased risk of breast carcinoma with regard to any histotype Citation[5–9,17].
The analyses of the association between different HRT regimens and ILC risk are limited and have not provided univocal results. Chen et al. observed that sequential and continuous combined HRT use was associated with an increased risk of ILC Citation[7]. Similarly, Li et al. substantiated that sequential and continuous combined HRT both increased ILC risk, whereas IDC risk remained nearly stable Citation[17].
Conversely, Dailing and coworkers reported that only continuous HRT was significantly correlated with an increased risk of ILC Citation[6]. However, overall, these data seem to suggest that sequential and continuous combined HRT may be equivalent with respect to the magnitude of ILC risk.
Diagnosis of ILC
The association between HRT use and ILC raises great concern for the diagnostic surveillance of those women who are taking HRT. The most challenging diagnostic issues of ILC are the early detection and the accurate assessment of tumor extension. The diagnostic difficulties derive from the linear ‘Indian file’ growth pattern of ILC, where tumor cells infiltrate the mammary parenchyma diffusely, thus causing a poor stromal reaction Citation[18]. For this reason, ILC is more frequently multicentric/multifocal and entails a higher incidence of synchronous and/or metachronous controlateral disease compared with IDC Citation[19].
As a result, both Mx and ultrasound have a lower sensitivity for detecting ILC compared with IDC. The sensitivity of Mx for the detection of ILC has been reported to range from 57 to 76% Citation[20], whereas the sensitivity of ultrasound varies from 25 to 88% Citation[21]. Owing to the peculiar growth pattern, ILC seldom appears as a nodular opacity but rather as an asymmetric density or an architectural distortion Citation[22].
In the last few years, MRI has become the most reliable tool for the detection of ILC. MRI is able to identify additional malignancy occult on Mx and separate from the primary tumor site or in the controlateral breast in up to 60% of patients with ILC Citation[23–25]. The high sensitivity of MRI has been demonstrated to affect the management of ILC remarkably. In several studies, ILC was treated with more extensive surgical procedures after MRI than was initially planned by conventional Mx and ultrasound Citation[26]. Conversely, the high false-positive rates of breast MRI, with an overall specificity ranging from 65 to 80%, lead to an increased number of invasive diagnostic procedures for benign diseases Citation[27,28]. In addition, some authors reported a higher risk for overestimating the lesion size on MRI Citation[29], while others observed that the lesion size is not overestimated more often than Mx Citation[28]. Nonetheless, the size overestimation in most cases has been attributed to extensive lobular carcinoma in situ in and around the ILC Citation[28].
Fine-needle aspiration (FNA) fails more frequently in ILC than in IDC, with false-negative rates ranging from 4 to 60% and with a sensitivity of 60–76% Citation[30]. The high false-negative rate has been attributed to inadequate sampling or poor cellularity, to difficulties in interpretation owing to the presence of only mild atypia, to the architectural arrangement of neoplastic cells according to ILC subtype, to cytopathologist’s experience, to the nuclear cellular grade and, finally, to the clinical size of the lesion Citation[30–32].
Management of ILC
The management of ILC is highly debated and available data are not univocal to provide thorough recommendations. Several studies have substantiated that ILC carries less aggressive biological features than IDC Citation[19,33,34]. Furthermore, it is accepted that breast cancer associated with HRT use has frequently low stage at diagnosis, probably owing to the higher clinical and mammographic breast surveillance of women taking HRT Citation[13,35].
Although these favorable characteristics clearly show that ILC and IDC are distinct entities, with different clinical courses and biological phenotypes, several studies did not observe significant differences in overall and disease-free survival between ILC and IDC Citation[19,31,33,36].
The choice of the most appropriate type of breast surgery is currently the most controversial issue concerning the treatment of ILC. Mastectomy rates are higher in patients with ILC because of the high incidence rates of multifocality/multicentricity, the difficult assessment of margins status at operation Citation[37,38], the larger size at diagnosis than IDC Citation[19,33,34] and, finally, the lower clinical and pathological responses to neoadjuvant chemotherapy Citation[39–41]. Nonetheless, breast conservative surgery is warranted by the introduction of MRI in the preoperative assessment of ILC extension and by the similar local recurrence rates after breast conservative surgery and mastectomy in patients with ILC Citation[42,43].
Sentinel node (SN) biopsy has been shown to be feasible and accurate for the axillary staging of patients with ILC Citation[44]. Some authors reported significant differences in the sensitivity of metastases detection depending on the method of pathologic detection. In the study by Chan et al., SN metastases were 10% less likely to be identified by frozen-section analysis, and 13% more likely to be detected by serial sections/immunohistochemistry Citation[45]. These results are probably due to the propensity of ILC to metastasize as isolated tumor cells and are consistent with the lower expression rates of the cell adhesion molecule E-cadherin in ILC Citation[46]. In the study by Creager, the use of imprint cytology did not show any difference in sensitivity, specificity or accuracy between ILC and IDC, whereas the sensitivity for detecting macrometastases in patients with ILC was higher than for detecting micrometastases Citation[47]. Conversely, in the series by Cox et al., the same method was associated with lower sensitivity rates for ILC compared with IDC Citation[48].
Conclusion
The association between HRT use and ILC has important clinical and surgical implications.
The diagnosis of ILC may be difficult since Mx and ultrasound both have lower sensitivity for the detection of ILC. In the last decade, MRI has proven to be a reliable tool for the detection of multifocal/multicentric lesions and for the preoperative surgical planning of patients with ILC.
Mastectomy is often the preferred surgical treatment of patients with ILC, in case of multifocal and multicentric disease, whereas breast conservative surgery should always be considered after preoperative breast MRI assessment. In the next few years, teomic and microarray technologies are expected to play a significative role to clarify the molecular mechanisms underlying the association between HRT use and lobular histotype as to better understand the effects of exogenous hormones on breast tissue in menopausal women.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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