Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome

Carcinoma of the breast is a histologically heterogeneous disease. Invasive lobular carcinoma (ILC) accounts for 8–14% of all breast cancers [1, 2]. Data from a recent epidemiologic study [3] indicate that for unknown causes the incidence of this type of breast cancer is increasing, especially among postmenopausal women.

The morphologic features of lobular carcinoma differ from those of ductal carcinoma. ILC is characterized by small, round cells that are bland in appearance and have scant cytoplasm, which infiltrate the stroma in single file and surround benign breast tissues in a targeted manner [1, 4]. Infiltration typically does not destroy anatomic structures or incite a substantial connective tissue response. By virtue of their distinctive growth pattern and biology, lobular carcinomas often fail to form distinct masses that can easily be diagnosed by palpation or mammography. This can make early diagnosis challenging [5, 6] and breast conservation approaches more difficult. Lobular carcinomas may have a substantially increased propensity for multifocal and multicentric distribution and for bilaterality [5, 7‐11]. Metastatic spread with an uncommon pattern of involvement has been reported [12, 13].

Because it is substantially less common than infiltrating ductal carcinoma (IDC), knowledge about the clinical outcome of lobular carcinoma has been based on studies including relatively small numbers of patients. Reported prognosis varies and has been reported to be worse [14, 15], no different [16‐19], or better [20] than that with IDC. This reported variability might be due to relatively small numbers of cases in each analysis. In addition, few data have been reported on the biologic features of lobular carcinomas within the context of their clinical outcome. We therefore undertook an extensive comparison of ILC and IDC using a large database to provide a more complete and reliable assessment of their biologic phenotypes and clinical behaviors, which might yield information useful for clinical decision making or for further exploring the biologic nature of this disease.

The present study demonstrates that ILC has distinctive clinical and biologic characteristics compared with IDC. Lobular carcinomas were more likely to occur in older patients; to be larger in size, ER and PgR positive, and diploid with a low S-phase fraction; and to have normal p53 status and low to absent EGFR and HER-2. The distributions of metastases were also different. Despite a substantially less aggressive biologic phenotype, recurrence and survival were very similar between ILC and IDC patients.

To our knowledge this is the largest published report on ILC that comprehensively evaluates biologic characteristics and clinical outcomes. The incidence of ILC observed in the present study (8.2%) is in accordance with the incidence range of 8–14% reported in the literature [1, 14, 31‐33]. In addition, the large number of patients, the multi-institutional nature of the study population, and the median follow-up period of more than 7 years strengthen the reliability of the results and permit extrapolation of the findings to routine clinical practice.

Clinical characteristics at diagnosis are different for ILC than for IDC. Several studies showed that patients with ILC are on average older at presentation than are IDC patients [18, 19, 34]. Consistent with these data, in the present study the median ages at diagnosis were 64.6 years for patients with ILC and 60.6 years for patients with IDC. This older age at diagnosis in those with ILC could be due to a low proliferative rate or greater difficulties in detecting ILC. In terms of tumor size, 14% of ILCs were found to exceed 5 cm as compared with only 9.1% of IDCs. The lack of a desmoplastic reaction may make the lesion impalpable and invisible, both clinically and mammographically, deferring the identification and probably explaining why lobular carcinomas were larger at diagnosis than IDCs. However, despite the slightly larger size of ILCs, the rate of lymph node involvement was the same in each group. The uniform appearance of bland tumor cells that lack cellular atypia and often have a low mitotic rate make the lobular carcinoma cells more difficult to detect in metastatic lymph nodes. Thus, particular attention should be given to histologic examination of axillary nodes in resection specimens of lobular carcinomas because nodal metastases are more often missed with ILCs, and false-negative results are more frequently reported compared with ductal carcinomas [35].

From this report it is evident that the metastatic pattern for ILC differs from that of IDC. ILC was less likely to affect the lungs, pleura, and CNS than was IDC. By contrast, the peritoneum, ovary, and gastrointestinal system were much more likely to be involved in advanced ILC. Entries for gastrointestinal involvement in the database represent peritoneal and parenchymal involvement. CNS metastases were more common with IDC. This database could not clearly distinguish between brain, spinal cord, or leptomeningeal metastases in its classification of CNS involvement. It has been reported that ILC more often involves the meninges and spinal fluid [13, 36‐38] but we were unable to address this issue directly because of limitations in the database. The factors that account for this distinct metastatic pattern are unclear. The difference could be due to a cell size or shape with physical properties that favor certain areas with microanatomy that is more conducive to stopping or trapping these types of cells. Alternatively, the microenvironment of the ovary or peritoneum may provide growth and survival factors that favor ILC cells over IDC cells. Additional molecular or biologic differences might account for this peculiar pattern of metastasis. It has been demonstrated that loss of expression of the cell–cell adhesion molecule E-cadherin in ILC may decrease adhesiveness of cells and facilitate this type of infiltration [19, 39, 40]. Indeed, the findings of this study support a different molecular biology of ILC.

Bilateral involvement is reported to be 20–29% in lobular carcinoma [10, 12, 16, 41, 42]. In our dataset the incidence of contralateral breast cancer in women with ILC was nearly double that in women with IDC. This finding could make a compelling case for the use of tamoxifen to prevent contralateral breast cancer in women with lobular primaries.

Because only a few small and scattered studies have addressed the biologic features of ILC, one of the main objectives of the present study was to characterize more comprehensively its biologic phenotype. This report definitively confirms and extends the findings of some previous studies [11, 12, 17, 43‐45] indicating that lobular carcinomas are significantly more likely to be steroid receptor positive than are IDCs. These results also demonstrate that lobular carcinomas are more likely to have low S-phase fractions and to be diploid. The evaluation of S-phase fractions in ILC in other published series confirms our findings [18, 20, 46]. Few reports have evaluated the well studied growth factor receptors HER-2 and EGFR, or the tumor suppressor gene p53 in ILC. In the present analysis, no more than 5–10% of tumors classified by a broad range of pathologists as ILC over-expressed EGFR and/or HER-2. Positivity for p53 was found half as often in ILC as in IDC. Only two small studies have analyzed these molecules in ILC [47‐49] and their results are similar to those reported here. The 5–10% of patients who were positive for HER-2 or EGFR, or who were p53 positive, may not have been of the classic ILC subtype but possibly a variant, such as those found in the pleomorphic or mixed ILC–IDC categories. ILC subtypes have been reported to have different biologic characteristics and clinical behavior as compared with the classic subtype [50‐52], but the difference has not found to be statistically significant, although the number of patients included in the various studies is small. Unfortunately, we were unable to subtype further those tumors with lobular histology. More study is needed on these specific subtypes. However, together these findings suggest that ILC is biologically different from IDC.

In general, the management of patients in this study with ILC was somewhat different from the management of patients with IDC. In practice, the histologic type appears to play a role in the choice of surgical procedure selected [11, 44, 53, 54]. This analysis suggested that ILC was treated by mastectomy slightly more frequently than was IDC. Although this tendency to favor mastectomy may be related to factors specific to the patient and/or surgeon, the choice for these procedures is also influenced by pathologic findings. Indeed, the diminished fibrotic reaction present in ILC makes it difficult for pathologists and surgeons to determine the gross extent of the disease during surgery, and to achieve tumor-free margins after a limited excision. With respect to systemic therapy, because lobular carcinomas are more frequently steroid receptor positive tumors, as expected a greater proportion of ILC patients than of IDC patients received adjuvant endocrine therapy.

From previous studies the prognosis for ILC compared to IDC is unclear. An important finding of the present large study is that the 5-year OS of patients with ILC is not different from that of patients with IDC. Therefore, the fact that ILC has more favorable prognostic factors does not translate into a survival advantage for patients with ILC. Although ILC is associated with a less aggressive phenotype, this is offset by lobular carcinoma being more difficult to detect early, either by clinical examination or mammography. Furthermore, the reported higher rate of false-negative lymph nodes by histologic examination in lobular carcinomas could cause a general under-staging of this histologic type at the time of surgery.

Multivariate analyses did not identify any prognostic differences associated with ILC or IDC. In these analyses, considering all ILC and IDC patients together, lymph nodes status, tumor size, age, S-phase, PgR status, and ER status were found to be associated with both recurrence and survival, but histology was not an important independent predictor of recurrence or survival. Furthermore, the same standard prognostic factors (tumor size, axillary nodal status, hormone receptors, S-phase, and age) used in ductal carcinoma are applicable in lobular carcinoma as well [55].

Results from this large dataset show clearly that ILC and IDC are different entities with different clinical courses and different biologic phenotypes, but no clinically meaningful differences in survival are evident. At present, both types of breast cancer should be managed similarly and histologic subtype (lobular or ductal) should not be a factor in the therapeutic decision-making process, and should not be considered an important prognostic or predictive factor at diagnosis. Emerging technologies such as high throughput genome mapping and microchip cDNA expression arrays may further elucidate molecular differences in these different types of breast cancer.