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Annals of Clinical & Laboratory Science 37:127-134 (2007)
© 2007 Association of Clinical Scientists

Expression of Cytokeratin Markers, ER-alpha, PR, HER-2/neu, and EGFR in Pure Ductal Carcinoma In Situ (DCIS) and DCIS with Co-existing Invasive Ductal Carcinoma (IDC) of the Breast

Sharon Steinman1, Jianmin Wang2, Patricia Bourne1, Qi Yang1 and Ping Tang1
1 Department of Pathology and Laboratory Medicine, University of Rochester Medical School, Rochester, New York, and 2 RTI Health Solution, Research Triangle Park, North Carolina

Address correspondence to Ping Tang, M.D., Ph.D., Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Box 626, Rochester, New York 14642, USA; tel 585 275 6640; fax 585 273 3637; e-mail: ping_tang{at}urmc.rochester.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Previously, we showed that pure ductal carcinoma in situ (DCIS) of the breast can be divided into 3 subtypes (luminal, basal/stem, and null) based on the expression of 5 cytokeratin (CK) markers: CK5/6, CK14, CK17 (stem/basal), and CK8, CK18 (luminal). The distributions of CK subtypes were associated with nuclear grade and differential expression of estrogen receptor-alpha (ER-{alpha}), progesterone receptor (PR), HER-2/neu, and epidermal growth factor receptor (EGFR). In this study, we further explore the expression patterns of CK markers, ER-{alpha}, PR, HER-2/neu, and EGFR by immunohistochemical (IHC) analysis of 99 cases of pure DCIS and 96 cases of DCIS with co-existing invasive ductal carcinoma (DCIS/IDC). We show that between high-grade DCIS and DCIS/IDC, there are differential expression patterns for ER-{alpha}, PR, and EGFR in corresponding CK subtypes, suggesting that at least some pure DCIS is molecularly distinct from DCIS/IDC. In most cases there is a high degree of co-expression of these markers between DCIS and the co-existing IDC, suggesting that DCIS is frequently a precursor lesion for co-existing IDC. The rate of discordant expression of these markers is low and is more frequently associated with high-grade carcinoma, suggesting that other molecular pathways also may also be present. There are significant differences in the expression of these molecular markers between high-grade and non-high-grade carcinomas, supporting the view that high-grade and non-high-grade carcinomas of the breast are molecularly distinct entities.

Keywords: breast carcinoma, IDC, DCIS, cytokeratin, ER-{alpha}, PR, HER-2/neu, EGFR


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Breast cancer is a heterogeneous disease that encompasses a wide range of pathological entities and clinical behaviors, thus posing great challenges in understanding the precise molecular mechanisms of breast carcinogenesis [1]. Historically, the progression of breast cancer has been viewed as a linear multi-step process, from hyperplasia, atypical hyperplasia, and carcinoma in situ, to invasive and metastatic carcinoma, supported by evidence from clinical, pathological, and genetic studies [2–3]. Recent reports suggest that breast carcinogenesis is a series of stochastic genetic events that lead to distinct and divergent pathways towards invasive carcinoma [4–7]. Nuclear grade of breast carcinoma is one of the key pathological features associated with clinical outcome and distinct genetic changes [8–9]. Reliance on ER-{alpha}, PR, and HER-2/neu expression to guide clinical management and to predict clinical outcome is far from satisfactory. Additional molecular markers are needed to predict clinical outcome and devise optimal individualized therapy [10–11].

Most breast carcinomas arise from terminal duct lobular units (TDLU). Several studies based on expression of cytokeratin (CK) markers have proposed that there are at least 3 distinct cell types present in TDLU: stem cells (expressing CK5/6), luminal glandular cells (expressing CK7/8/18/19), and basal myoepithelial cells (expressing CK14, 17, SMA), along with 2 intermediate cell populations with dual expression of either stem and luminal cell markers (CK5/6, CK8, CK18) or stem and basal cell markers (CK5/6, CK14, CK17) [12–13]. Furthermore, expression of CK5 and/or CK17 seems to correlate with poor clinical outcome in a subgroup of invasive breast carcinomas [14,15].

We showed previously that high-grade and non-high-grade pure DCIS can each be sub-classified into 3 CK subtypes (luminal, stem/basal, and null) and that the distribution of the CK-subtype is strongly correlated with nuclear grade (ie, high grade DCIS is associated with basal/stem subtype) [16]. These findings suggest that different progenitor cell types contribute to the heterogeneity of breast carcinomas. Furthermore, CK-subtypes are associated with differential expression patterns of ER-{alpha}, PR, HER-2/neu, and epidermal growth factor receptor (EGFR), even within the same nuclear grade [17]. The expression of ER-{alpha} and PR is seen in all 3 subtypes of high-grade and non-high-grade DCIS. HER-2/neu over-expression is seen in all 3 subtypes of high-grade DCIS, but only in the luminal subtype of non-high-grade DCIS [17]. EGFR expression is infrequent, positive only in the luminal type of high-grade DCIS, and independent of ER-{alpha}, PR, and HER-2/neu expression.

In this study we explore the expression patterns of these markers in pure DCIS and DCIS/IDC to gain better understanding of the precise relationships between pure DCIS and co-existing DCIS/IDC and to identify potential molecular markers for prognostic, therapeutic, and preventive purposes.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Immunohistochemical stains.  Tissue samples from 96 cases of DCIS/IDC and 99 cases of pure DCIS in the tissue archives of the Pathology Department at Strong Memorial Hospital (Rochester, NY) were divided into non-high-grade and high-grade subgroups using standard nuclear grading criteria [18,19]. IHC staining was performed with various antibodies (Table 1Go) on formalin-fixed paraffin-embedded tissue obtained from one representative section of each case. Pretreatments consisted of enzyme digestion or other heat-mediated retrieval methods. The sections were stained with a Dako Autostainer using Envision Plus–HRP polymer (Dako Corporation, Carpenteria, CA), horse anti-mouse IgG-biotin (Vector Labs, Burlingame, CA), streptavidin-HRP (Jackson Labs), and AEC (Dako), and were counterstained with hematoxylin. Positive stains were defined as ≥10% of tumor cells with strong cytoplasmic stain for CK markers; 3+ membrane stain for HER-2/neu and EGFR, and any intensity of nuclear stain for ER-{alpha} and PR.


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  		Table 1. Specifications of the clones, sources, pretreatment conditions, and dilutions of the primary antibodies.
 
Statistical analyses.  Concordance of expression of CK markers, ER-{alpha}, PR, HER-2/neu, and EGFR between DCIS and its co-existing IDC was measured by Cohen’s kappa coefficient [20]. Kappa equals +1 when there is complete concordance between DCIS and co-existing IDC. When the observed concordance exceeds chance concordance, kappa is positive and its magnitude reflects the strength of concordance. Fisher’s exact test was used to determine if there was true concordance between 2 proportions. Calculations were performed with SAS software (SAS, Inc., Cary, NC).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In TDLU of normal breast tissue, ER-{alpha} and PR showed scattered positivity and HER-2/neu was negative. EGFR was expressed in normal myoepithelial cells with variable intensity as previously reported [21]. The antibodies to CK5/6, CK14, and CK17 stained basal cells, while the antibodies to CK8 and CK18 stained luminal cells.

CK-subtypes identify differential expression patterns of ER-alpha, PR, and EGFR between high grade DCIS/IDC and pure DCIS.  As shown in Table 2Go, non-high-grade carcinomas were frequently positive for ER-{alpha} and PR in all 3 subtypes of both DCIS/IDC and DCIS with similar frequency. The expression patterns of ER-{alpha} and PR in high-grade carcinomas were different. They were expressed in all 3 subtypes of pure DCIS, but only in the luminal subtype of DCIS/IDC. For EGFR, a subtype-dependent expression pattern was also observed. EGFR was only present in luminal subtype of high grade DCIS and only in basal/stem subtypes of high grade DCIS/IDC. For HER-2/neu, on the other hand, the expression patterns were similar in DCIS/IDC and DCIS of both high-grade and non-high-grade carcinoma. It was positive only in luminal subtype of non-high-grade carcinoma, but in all 3 subtypes of high-grade carcinoma.


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  		Table 2. The relationship between nuclear grade, CK cell origin subtypes, and expression of ER-{alpha}, PR, HER-2/neu, and EGFR in DCIS/IDC versus pure DCIS; (the data for DCIS/IDC and for pure DCIS are expressed as no./no., or as %/%).
 
High degree of co-expression is present between DCIS and co-existing IDC.  As shown in Table 3Go and Fig. 1Go, panels A–J, in each case, the rate of co-expression between DCIS and its co-existing IDC among all markers was high, ranging from 92.30% (48/52 for ER-{alpha}) to 100% (52/52 for HER-2/neu, EGFR, CK14, and CK17) for non-high-grade carcinoma, and 88.63% (39/44 for CK8 and 18) to 97.72% (43/44 for CK5/6) for high-grade carcinoma. Positive kappa coefficients and their p values (<0.05) indicated that there was true concordance between DCIS and its co-existing IDC for the expression of CK markers, ER-{alpha}, PR, HER-2/neu, and EGFR.


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  		Table 3. Comparison of co-expression of CK markers, ER-{alpha}, PR, HER-2, and EGFR in non-high-grade versus high-grade DCIS/IDC.
 

Figure 1
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  		Fig. 1. Co-expression and discordant expression in non-high-grade and high-grade DCIS/IDC (original magnification 400X). A–J: Examples of co-expression of several markers between coexisting DCIS and IDC in non-high-grade carcinoma. Non-high-grade DCIS (A) and IDC (B) stained with H&E. Non-high-grade DCIS (C) and IDC (D) co-express ER-{alpha}. Non-high-grade DCIS (E) and IDC (F) do not express CK-5/6. Non-high-grade DCIS (G) and IDC (H) co-express CK8. Non-high-grade DCIS (I) and IDC (J) do not express CK17. K–T: Examples of discordant expression of several markers between coexisting DCIS and IDC in high-grade carcinoma. High-grade DCIS (K) and IDC (L) stained with H&E. High-grade DCIS (M) expresses ER-{alpha} while IDC (N) does not express ER-{alpha}. High-grade DCIS (O) does not express CK-5/6 while IDC (P) does express CK-5/6. High-grade DCIS (Q) does not express CK-8 while IDC (R) expresses CK8. High grade DCIS (S) does not express CK-17 while IDC (T) expresses CK17.

 
Rate of discordant expression is low, and more frequent in high grade DCIS/IDC.  As shown in Table 3Go and Fig. 1Go, panels K–T, the discordance in expression of these molecular markers ranged from 0% (0/52 for HER-2, EGFR, CK14, and CK17) to 7.69% (4/52 for ER-{alpha}) for non-high-grade DCIS/ IDC, and 2.27% (1/44 for CK5/6) to 11.36% (5/44 for CK8 and CK18) for high-grade DCIS/IDC. Patterns of discordant expression for ER-{alpha} and PR were consistent; positive in DCIS component and negative in its co-existing IDC. For other markers, less consistent patterns were observed with positive or negative expression in either DCIS or IDC component of the same tumor. In non-high-grade carcinomas, 8 cases showed discordant expression, 4 of which showed discordance of 2 different markers (1 for ER and PR; 2 for CK8 and CK18; and 1 for ER and CK18). In high-grade carcinoma, 15 cases showed discordant expression, 4 of which showed discordance with 2 or more markers (1 for CK8 and CK18; 1 for EGFR and CK18; 1 for all 5 CK markers; and 1 for ER and PR).

Different expression patterns are present between non-high-grade and high-grade DCIS/IDC.  As shown in Table 4Go, the expression of ER-{alpha} and PR was more frequently associated with non-high grade carcinoma (p <0.0001 for both receptors), while the expression of HER-2/neu, EGFR, stem cell marker CK5/6, and basal cell markers CK14/ CK17 was more frequently associated with high-grade DCIS (p values from 0.0023 to 0.032). Luminal cell markers CK8 and CK18 showed no difference in expression pattern between high-grade and non-high-grade carcinomas (p values 1.00 and 0.27, respectively).


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  		Table 4. Expression of CK markers, ER-{alpha}, PR, HER-2, and EGFR in high-grade versus non-high grade DCIS/IDC.
 
Within the same nuclear grade, expression patterns are similar between DCIS/IDC and pure DCIS.  As shown in Table 5Go, the similarity of expression of these markers was significant within each nuclear grade between DCIS and DCIS/IDC. Non-high-grade DCIS/IDC had similar expression patterns as non-high-grade DCIS for all 9 markers. The same was true for high-grade DCIS/IDC and pure DCIS.


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  		Table 5. Comparison of expression patterns of CK markers, ER-{alpha}, PR, HER-2/neu, and EGFR in high-grade and non-high-grade DCIS/IDC and pure DCIS.
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The carcinogenesis of breast carcinoma is poorly understood. Recent studies suggest that several distinct pathways exist between hereditary and sporadic carcinomas, between high-grade and low-grade carcinomas, and between ductal and lobular carcinomas [5,22,23]. Loss of 16q is frequently associated with the pathway to low-grade DCIS [8]; gain of 17q12 is associated with the pathway to high-grade DCIS [24]; gain of 11q13 (cyclin D) is an early event that distinguishes carcinoma from benign hyperplasia [25]. Stem cell and progenitor cell research for breast carcinoma has received considerable attention. Normal breast epithelium can be divided into luminal cells, basal cells, and stem cells with morphological and immunological criteria [26,27]. Ttransformation of various types of progenitor cells contributes greatly to the heterogeneity of breast carcinoma. DCIS can be sub-classified into several cell origin-related CK subtypes [16], and the distribution of these subtypes is associated with nuclear grade and the expression patterns of ER, PR, HER-2/neu, and EGFR [17]. Expression of the basal/stem CK markers is associated with poor clinical outcome in invasive carcinoma [14–15].

Studies of patients with DCIS, who were initially misdiagnosed as benign lesions and did not receive treatment, indicate that the progression rate from DCIS to IDC ranges from 10 to 50% with up to 30-year follow-up [28,29]. A recent report shows that 11/28 (39%) patients with low-grade DCIS, treated with biopsy only, developed IDC in the same quadrant of the breast 3 to 42 years later [30]. It is clear that not all DCIS will progress to IDC during the patient’s lifetime. Identification of this low-risk subgroup of DCIS and establishing the factors that influence the progression of DCIS to IDC is essential for optimal clinical management of these patients.

Giardinas et al [31] used morphometry to compare the nuclei isolated from pure DCIS with those from the DCIS component of DCIS/IDC and concluded that these two categories of nuclei were significantly different. Park et al [32] found that although there was good concordance of expression of HER-2/neu between co-existing DCIS and IDC, there was a significant difference in HER-2/neu expression between pure DCIS and DCIS/IDC. Farabegoli et al [33] found that pure DCIS and DCIS/IDC are genetically distinct, based on comparisons of 15 microsatellite markers with loss of heterozygosity (LOH) analysis. In the current study, differential expression patterns of ER, PR, and EGFR were found between different CK subtypes of high-grade DCIS and DCIS/IDC, which also suggests that the subsets of DCIS and DCIS/IDC may be different molecularly. This difference may indicate that either: (a) pure DCIS is an earlier lesion than DCIS/IDC, but does not have all necessary genetic changes needed for progression to IDC; or (b) some pure DCIS are genetically programmed to be DCIS only. The latter hypothesis is favored because only a proportion of patients with DCIS progress to IDC even after long-term follow-up [28,29] and breast carcinoma has a stable genetic make-up during the progression from in situ to invasive and metastatic carcinoma [34]. Similarly, comparisons of pure IDC and DCIS/DCIS also suggest that they may be different entities biologically and genetically [35,36]. Mylonas et al [35] observed significantly different expression patterns of HER-2/neu, ER, and Ki67 in pure IDC versus IDC/DCIS. Jo and Chun [36] showed that pure IDC has a worse prognosis than IDC/DCIS. Thus, it appears that several distinct genetic pathways are not only involved in the development of high-grade and low-grade carcinoma, but are also involved in the development of pure DCIS, DCIS/IDC, and pure IDC, respectively.

The high rate of co-expression between DCIS and its co-existing IDC for CK markers, ER-{alpha}, PR, HER-2/neu, and EGFR in the current study supports the concept that DCIS is the most likely precursor lesion for its co-existing IDC. DCIS and IDC frequently co-exist within the same tumor and have the same nuclear features and genetic alternations [38,39]. The rate of discordant expression of all markers is low and discordant expression is frequently associated with high-grade carcinoma, suggesting that DCIS is often, but not always, a precursor lesion for its co-existing IDC. IDC may evolve de novo or through alternative pathways, especially in high-grade breast carcinoma. With the individual variability of expression of these molecular markers even within the same nuclear grade, molecular studies are critically necessary in each breast carcinoma to ensure optimal individualized therapy.

Significantly different expression patterns of ER, PR, HER-2/neu, EGFR, and CK markers were observed between high-grade and non-high-grade carcinomas, supporting the concept that high-grade and non-high-grade carcinomas evolve through distinct pathways. Similar distributions of CK-subtypes (luminal, basal/stem, and null) and similar expression patterns of ER-{alpha}, PR, HER-2/ neu, and EGFR between pure DCIS and DCIS/ IDC were observed within the same nuclear grade, suggesting that pure DCIS may be an earlier lesion than DCIS/IDC of the same grade.

More studies are needed to elucidate the precise relationships between pure DCIS and DCIS/IDC, to gain a better understanding of breast carcinogenesis, and to identify the aggressive subtypes of pure DCIS.


   Acknowledgments
 
The authors thank Steven I. Hajdu, M.D., for his invaluable advice and Marj Phillips and Tri Luong for their technical support.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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