Invasive ‘breast cancer’ represents a heterogeneous group of distinct entities that vary widely in terms of their morphologic spectrum, tumor biology, clinical presentation and behavior. Roughly 25% of invasive breast tumors can be recognized as ‘special histologic types’ based on distinctive cytologic features and growth patterns. While these ‘special type’ tumors have demonstrated considerable prognostic significance in clinical studies, little attention has been paid to the molecular genetic basis for these histologic entities in recent attempts at molecular classification of breast cancer, which have been derived primarily from the study of invasive ductal carcinoma of no specific type (IDC NOS). The integration of the histologic special types of breast cancer into current molecular classification schemes may have important prognostic and predictive implications for clinical management. It is also unclear at present whether prognostic gene sets, including the 70-gene prognosis profile
23 and 21-gene recurrence score
24 have similar prognostic power when applied to the special types of breast cancer. Weigelt et al
18,25 demonstrated that classic ILC and tubular carcinomas showed similarities at the level of gene expression and immunohistochemical profiles, falling into a luminal subtype, with low levels of e-cadherin expression distinguishing ILC. Such tumors would be expected to demonstrate expression of ER and to have a more indolent clinical course of disease.
Initial evidence for molecular subtypes of breast carcinomas came from a cDNA-microarray study of gene expression, which divided tumors into basal-like, luminal A, luminal B, HER2 over-expression, and normal breast-like subgroups, each with distinct clinical outcomes.
26–28 In an effort to develop a similar classification that is clinically significant, technically simple, reproducible and readily available, several IHC-based molecular classifications for breast cancer have been investigated extensively. These include: 1) Cytokeratin-based classification divides breast carcinomas into basal subtype (CK5/6, CK14, CK17 positive), and luminal subtype (CK8, CK18 positive and basal negative);
29–33 2) ER, PR and HER2-based classification defines the basal subtype as an absence of expression of ER, PR and HER2;
34–38 3) ER, HER2, EGFR and CK5/6-based classification
22,39 defines the basal subtype as ER and HER2 negative, and CK5/6 and/or EGFR positive, with 76% sensitivity and 100% specificity, respectively, compared to basal subtype defined by gene expression profiling. Although these IHC-based molecular classifications all show basal subtype has the worse prognosis, they are not interchangeable.
40 In addition to various definitions with similar terminology for molecular classification, other limitations for IHC-based molecular classifications include differences in patient cohorts, tumor grades, antibody methodology, and definition of positive staining for each marker.
Fadare et al
19 used one basal marker (CK5/6) to study 82 cases of invasive lobular carcinoma, and observed that 17% of the cases expressed CK5/6. In contrast, we did not identify any expression in any of our cases by any of the three basal cytokeratin markers (CK5/6, CK14 and CK17). In Fadare et al’s study, CK5/6 was considered as immunologically reactive if there was cytoplasmic staining unequivocally above the background, similar to our definition of positive staining for any CK marker. 8/14 of their cases showed strong diffuse and intense stain, while the other 6 remaining cases showed patchy and intense stain. Our study used the same monoclonal antibody for CK5/6 as was used by Fadare et al purchased from the same vendor. Our experience of IHC analysis on CK5/6, CK14 and CK17 positive cases of IDC has been that most cases present with strong patchy stains while only a few cases present with strong and diffuse stain. The reason for the different observation could be due to the number of pre-analytical variables between our two laboratories. Another less likely possibility would be due to differences in the patient population included in these two studies.
About 20 years ago, Eusebi et al
41 showed that PLC is a more aggressive tumor with apocrine differentiation. Since then many studies have focused on this more aggressive subtype of ILC. Buchanan et al
42 have found that pleomorphic lobular carcinomas are larger tumors, have more positive nodes, more frequently develop metastatic disease, and more often require mastectomies. By gene expression profiling, classic ILC falls into the luminal subtype,
25 while PLC may be of luminal, HER2 or molecular apocrine subtype by expression profiling, although PLC seems to share a common molecular genetic pathway with classic lobular carcinomas.
43–45 Although histologic subtype was not- mentioned in the report by Fadare et al
19 they did mention the correlation between CK5/6 expression and ER negativity, high histologic grade, and high mitotic index, suggesting some of their cases were likely to be pleomorphic ILC. There are 5 pleomorphic lobular carcinomas in our study, and none of them expressed any of the three basal CK markers. Pleomorphic ILC consists of 9.4% of all lobular carcinomas in our study, comparable with a rate of 10.8% observed by Buchanan et al
42 in a much larger study; 2 of them (40%) over-express HER2, compatible with a prior study by Frolit et al
46 who found 53% of PLC over-expressed HER2.
In summary, although one prior study suggested that a significant portion of invasive lobular carcinomas express basal cytokeratin markers,
19 our study with three commonly used basal cytokeratin markers failed to confirm their findings. It is very possible that we have not studied enough cases to make a conclusion, but it is unlikely that the level of basal CK marker expression would reach 17%. More studies are needed to investigate the molecular classification in lobular lesions.
