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Morphological and immunohistochemical characteristics of triple negative and basal breast carcinoma

Salman, Manal I.; Elhefnawy, Nadia G.; Shash, Lobna S.

Egyptian Journal of Pathology: July 2012 - Volume 32 - Issue 1 - p 6–13
doi: 10.1097/01.XEJ.0000417553.95276.37
ORIGINAL ARTICLES
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Introduction Molecular classification of breast carcinoma offers much better characterization of breast tumours and identifies the basal subtype, which has been studied extensively because of its unique prognostic implications.

Objective To identify basal breast carcinoma among triple-negative tumours [oestrogen receptor (ER), progesterone receptor (PR) and Her2neu negative] by immunohistochemical expression of cytokeratin 5/6 (CK5/6) and/or epidermal growth factor receptor (EGFR) and to study their morphological characteristics.

Materials and methods The study included 34 cases of breast ductal carcinoma with a triple-negative immunophenotype (ER, PR and HER2neu negative) that were received at the pathology departments of Ain Shams University Hospitals. Clinical data were retrieved from the archival files and all cases were subjected to a histopathological evaluation as well as immunohistochemical staining for CK5/6 and EGFR. Cases with focal clear cell change (six cases) as well as spindle cell change (three cases) were also stained for S100.

Results Among the 34 triple-negative cases, 20 cases (58.8%) were considered of the basal subtype as they expressed CK5/6 (52.9%) and/or EGFR (52.9%). Combined positivity for both markers was found in 80% of the positive cases. The main histological subtype in the study was invasive duct carcinoma not otherwise specified, with fewer percentages of medullary, mucinous and squamous subtypes. Negative lymph node status was predominant in the entire group and particularly in the basal group. Ductal carcinoma in situ was found in 35.3% of all cases and in 40% of the cases in the basal group. The salient morphological characteristics of the entire triple-negative group as well as the basal group included pushing tumour border, geographical tumour necrosis, central scar, prominent lymphoplasmacytic infiltrate, high tumour grade and sheet-like and ribbon growth patterns. Focal clear cell change as well as focal spindle cell change were also found in 30 and 15%, respectively, of the cases in the basal group.

Conclusion Triple-negative and basal breast carcinoma had some common morphological criteria that were more often encountered in the basal subtype; however, they are not diagnostic for the basal phenotype, and therefore, immunohistochemical staining for CK5/6 and/or EGFR is useful for the identification of such tumours.

Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Correspondence to Manal I. Salman, Pathology Department, Faculty of Medicine, Ain Shams University, 8888 Cairo, Egypt Tel: +20 100 604 9309; e-mail: manalsalman@live.com

Received October 7, 2011

Accepted October 23, 2011

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Introduction

Human breast carcinomas represent a heterogeneous group of tumours, which are diverse in their natural history, their outcome and their responsiveness to treatment (Ahr et al., 2001; Zhang et al., 2003). Breast cancer is a major health problem in developed countries. For many years, different classifications of the disease have been used for guiding the management of the patients (Charafe-Jauffret et al., 2005).

Molecular markers, such as the oestrogen receptor (ER) and the progesterone receptor (PR), and expression of the growth factor receptor HER2neu provide therapeutic predictive value, and are very important for the clinical management of breast cancer (Perou et al., 2000). The expression level and staining patterns of these markers are useful in predicting which tumours will respond to specific therapies; tamoxifen is used to treat only ER-positive tumours and herceptin is used to treat Her2neu-overexpressing tumours (Henson et al., 1995; Allred et al., 1998; Van de Rijn et al., 2002). Triple-negative or the so-called basal type does not benefit from such lines of therapy (Nielsen et al., 2004). Kreike et al. (2007) pointed out that being deprived of the chance of the adjuvant endocrine treatment, these patients should undergo adjuvant chemotherapy treatment.

New classifications considering ER, PR and Her2neu receptors status have evolved and have been of considerable clinical value. The largest difference in the overall gene expression profile is observed among the ER-positive and the ER-negative breast cancer subtypes (Perou et al., 2000). Nonetheless, many other genes are currently being identified; the identification of such genes has limited the clinical value of the ‘ER, PR and Her2neu’ panel, therefore, the subclassification of breast cancers on the basis of this panel still provides incomplete prognostic and predictive information (Buerger et al., 2001).

Recent gene expression profiling of breast cancer has identified specific subtypes with clinical, biologic and therapeutic implications. The basal-like group of tumours is one of these subtypes distinguished by an expression signature similar to that of the ‘basal/myoepithelial stem cells’ of the breast (Rakha et al., 2007).

Basal-like breast cancer has been characterized extensively on the basis of gene expression profiles. Cost and complexity issues have rendered gene expression profiling impractical for application as a routine hospital diagnostic tool. It is becoming increasingly necessary for these tumours to be defined on the basis of immunohistochemical (IHC) staining patterns.

The IHC panel that best defines basal-like tumours is under investigation and various combinations of ER negative, PR negative, HER2neu negative, cytokeratin 5/6 (CK5/6) positive and epidermal growth factor receptor (EGFR) positive have been tested. It is now known that the inclusion of positive markers (EGFR and CK5/6) for the diagnosis of the basal phenotype results in a better identification of these tumours with a close match with that of its gene signature (Tischkowitz et al., 2007; Cheang et al., 2008).

Selection of breast cancer cases with negative immunostaining for ER, PR and Her2neu, but positive immunostaining for either CK5/6 or EGFR, allows pathologists to identify the basal subtype with 76% sensitivity and 100% specificity. Although EGFR expression alone is not a basal-like breast cancer-specific marker, nevertheless, as it is expressed in basal breast cancers, when combined with other markers, it considerably aids the IHC identification of these tumours (Nielsen et al., 2004; Paredes et al., 2006).

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Aim of the work

The aim of this work is to identify the basal variant of breast carcinoma cases among the triple-negative cases (ER, PR and Her2neu negative) by IHC expression of CK5/6 and/or EGFR and to study the morphological criteria of both groups.

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Materials and methods

The present study included 34 cases previously diagnosed as ductal breast carcinoma with a triple-negative immunophenotype (ER, PR and HER2neu negative) collected from the pathology departments of Ain Shams University Hospitals.

Archival files of the patients were examined to record:

  • Age of the patient.
  • Type of operation [modified radical mastectomy (MRM) or lumpectomy operation]; in our study, 19 cases were MRM specimens and 15 cases were lumpectomy specimens.
  • The pathologic data assessed included:
    • Size of the tumour.
    • Regional lymph node (LN) status in terms of the absence or presence of metastatic tumour deposits in the MRM cases.
    • Tumour border: infiltrative versus pushing border, where the tumour border was considered pushing when observed in all tumour sections with the absence of any infiltrative foci.
    • Presence of geographical tumour necrosis.
    • Central scar formation.
    • Prominent lymphoplasmacytic infiltration.
    • Tumour histologic subtype.
    • Tumour growth architecture; syncytial sheet-like growth pattern if present.
    • Presence of an in-situ ductal component and specification of its type and its percentage from the tumour bulk.
    • Cell morphology: polygonal, spindle, squamous, clear cell, etc.
    • Tumour grade according to the ‘Nottingham modification of Bloom Richardson scoring system’.
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Immunohistochemical staining

For IHC staining, sections of 4–5 um thickness were cut from the paraffin blocks of the tumours on poly-L-lysine-coated slides. IHC staining was performed according to the standard immunoperoxidase method described by Hsu et al. (1981), using ready-to-use primary mouse monoclonal antibodies for CK5/6 (Zymed, California, USA) and EGFR (Zymed), and an Ultravision Plus Detection System (Fremont, California, USA). Anti-polyvalent, HRP/DAB, (ready-to-use; Zymed) was used. S100 staining was applied only in nine cases, six with focal clear cell changes and three with a focal spindle cell morphology, to check for possible pure myoepithelial differentiation, utilizing a mouse monoclonal antibody for S100 (Labvision, Fremont, California, USA).

CK5/6-positive staining was considered when found in the cytoplasm of at least 10% of the tumour cells. EGFR-positive staining was considered when found in the cell membrane and/or the cytoplasm of at least 10% of the tumour cells (Nielsen et al., 2004; Bhargava et al., 2009).

S100-positive staining was considered when found in the cytoplasm of the majority of the cells (Bassler and Katzer., 1992).

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Results

Among the 34 cases of triple-negative breast carcinoma cases included in the study, 20/34 cases were assigned to the basal breast carcinoma (BBC) group (defined by positive staining results for CK5/6, EGFR or both), accounting for 58.8% of the total triple-negative tumours. CK5/6 staining was observed in 18/34 of cases (52.9%), EGFR staining was observed in 18/34 cases (52.9%) and combined staining was observed in 16/34 cases (47.1%), and in 16/20 of all BBC cases (80%).

The age of the patients ranged from 40 to 79 years, with a mean age of 54.4 years. The tumour size ranged from 1 to 11 cm, with a mean size of 4.4 cm. Axillary LN metastases were found in 9/19 cases (47.4%) of all the MRM specimens and in 6/14 cases (42.9%) of the BBC group mastectomy specimens.

In terms of the tumour histologic subtype, ductal carcinoma of the not otherwise specified (NOS) type accounted for 27/34 cases (79.4%) and 14/20 cases (70%) of the BBC group (Fig. 1a and b); one case, 1/34 (2.9%), was a metaplastic squamous cell carcinoma and it also belonged to the BBC group 1/20 (5%) (Fig. 1c and d), medullary carcinoma accounted for 3/34 cases (8.8%) and for 2/20 cases (10%) of the BBC group (Fig. 1e and f), and the mucinous subtype represented 3/34 cases (8.8%) and they belonged to the BBC group 3/20 (15%) (Fig. 1g and h).

Fig. 1

Fig. 1

In terms of the tumour grade, 27/34 cases (79.4%) were grade II and 7/34 cases (20.6%) were grade III; among the BBC group, 15 cases (75%) were grade II and five cases (25%) were grade III.

In terms of the morphological characteristics of the studied cases, an infiltrating tumour border was found in 25/34 cases (73.5%) and in 13/20 cases of the BBC group (65%) (Fig. 2b), whereas a pushing border was recorded in 9/34 cases (26.5%) and in 7/20 cases (35%) of the BBC group (Fig. 2a). Geographical tumour necrosis was recorded in 25/34 cases (73.5%) and in 15/20 cases (75%) of the BBC group (Fig. 2c). A central scar was present in 4/34 cases (11.8%) and in 3/20 cases of the BBC group (15%) (Fig. 2d).

Fig. 2

Fig. 2

A marked lymphoplasmacytic reaction was found in 15/34 cases (55.9%) and in 13/20 cases (65%) of the BBC group (Fig. 2e). A ductal carcinoma in-situ component (DCIS) was found in 12/34 cases (35.2%) and in 8/20 cases (40%) of the BBC group, including comedo, solid, cribriform, clinging and micropapillary types. The comedo type was the most prevalent type in all BBC cases (Fig. 2g and h)

In terms of the tumour architecture, a sheet-like growth pattern was found in 17/34 cases (50%) and in 11/20 cases of the BBC group (55%), a ribbon-like growth pattern was seen in 4/34 cases (11.8%) and in 1/20 BBC case (5%), a combined sheet-like and ribbon-like growth pattern was found in 1/34 case that belonged to the BBC group (Fig. 2f), whereas a nondescript growth pattern was seen in the rest of the cases.

In terms of the tumour cell morphology, a polygonal cell morphology was seen in all cases. Bizarre tumour cells and tumour giant cells with marked nuclear atypia and mitotic activity were found in grade III cases (Fig. 2i and j).

Focal clear cell change was noted in 6/34 cases (17.6%); all of them belonged to the BBC group (30%) and they also showed positive immunostaining for S100 (Fig. 3a–c). Focal spindle cell morphology was found in 3/34 cases (8.8%); all of them belonged to the BBC group (15%) and they also showed positive immunostaining for S100 (Fig. 3d–f). Focal or global squamous differentiation was found in 6/34 cases (17.6%); all of them also belonged to the BBC group (30%) (Fig. 1c and d).

Fig. 3

Fig. 3

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Discussion

Human breast cancers are heterogeneous in their morphology, clinical course and response to therapy. This heterogeneity may be because of differences in the underlying target cell population and/or it may be the result of different combinations of mutations in a normal breast stem cell or committed progenitor cell (Gusterson et al., 2005).

Recent gene expression profiling of breast cancer has identified specific subtypes with clinical, biologic and therapeutic implications. The basal-like group of tumours is one of these subtypes distinguished by an expression signature similar to that of the ‘basal/myoepithelial stem cells’ of the breast (Rakha et al., 2007).

The IHC panel that best defines basal-like tumours is under investigation and various combinations of ER negative, PR negative, HER2neu negative, CK5/6 positive and EGFR positive have been tested. It is now known that inclusion of positive markers (EGFR and CK5/6) for the diagnosis of the basal phenotype leads to a better identification of these tumours with a close match to that of its gene signature (Tischkowitz et al., 2007; Cheang et al., 2008).

Basal-like breast cancer is a distinct group of tumours that is associated with a poor clinical outcome. Identification of these lesions and their differentiation from other ductal carcinomas are necessary for their proper management (Rakha et al., 2008).

BBCs may require different chemotherapy regimens or more aggressive therapeutic regimens and may need to be identified specifically in laboratory research designed to identify new therapeutic targets (Turner et al., 2004).

Tsuda et al. (2005) reported that among the basal category of triple-negative tumours, the examination of c-kit and EGFR overexpressions is not only useful for understanding their cellular origin and biological behaviour but also of clinical importance for individualization of therapeutic strategies. Several new drugs that target the EGFR in breast cancer are currently being evaluated and the current observations suggest that the effects of these drugs may become more apparent over the longer term (Wakeling, 2005).

Paredes et al. (2006) reported that nowadays, EGFR is a valid target in cancer therapy in both colon cancers and non-small-cell lung carcinomas. Moreover, Livasy et al. (2006) and Siziopikou and Cobleigh (2007) proposed that EGFR-targeted therapy is an option for some of the basal breast tumours.

The present study included 34 cases previously diagnosed as ductal breast carcinoma with a triple-negative immunophenotype (ER, PR and HER2neu negative). Twenty out of 34 cases were diagnosed as BBC on the basis of their IHC expression of EGFR and/or CK5/6.

In terms of the tumour size in the current study, it ranged from 1 to 11 cm, with a mean size of 4.3 cm among all cases as well as among the basal group. The majority of cases were more than 2 cm. Concordant results were reported by Foulkes et al. (2004), Lerma et al. (2007) and Kreike et al. (2007), who reported that the majority of these tumours were larger than 2 cm. Rakha et al. (2007) attributed the large tumour size to the rapid rate of growth of these tumours.

In terms of the LN status, regional nodal metastasis accounted for 47.4% of all MRM cases; six of them belonged to the basal group, representing 30% of MRM cases of the that group. Thus, in this study, the absence of LN metastasis predominated in all cases particularly in the basal group. This finding is in agreement with that of Nielsen et al. (2004), who detected regional nodal metastasis in only 39% of BBC cases. Furthermore, Kreike et al. (2007), Tischkowitz et al. (2007) and Bhargava et al. (2009) studied the entire triple-negative group and reported that triple-negative tumours show a low tendency for LN metastasis. The paucity of nodal metastasis among the triple-negative tumours including basal carcinoma may be attributed to their relation to the BRCA1 gene. Tumours harbouring a BRCA1 signature have been reported in the literature to be more commonly LN negative (Oldenburg et al., 2006).

In terms of the tumour histologic subtype, 79.4% of cases included in this study were the invasive duct carcinoma ‘NOS’ type, accounting for 70% of the basal group. Concordant results have been reported by Korsching et al. (2004), Livasy et al. (2006) and Rakha et al. (2008). Metaplastic squamous cell carcinoma represented 2.9% of the cases in this study and it belonged to the basal group, accounting for 5% of its cases. Concomitant findings were also reported by Livasy et al. (2006), Kreike et al. (2007) and Lerma et al. (2007) as metaplastic carcinoma accounted for 9% of cases in the first two studies and for 3% of cases in the third study.

Moreover, three cases were diagnosed as medullary carcinoma in the current study, representing 8.8% of all cases and 10% of the basal cases. Two of these cases (66.67%) belonged to the basal group. Similarly, Jacquemier et al. (2005) reported a basal phenotype in 94% of their medullary cases, and Vincent-Salomon et al. (2007) found that 93% of medullary tumours had a basal immunophenotype.

However, a mucinous subtype was observed in 8.8% of all cases of this study and in 15% of the basal group. Yet, it was not reported in the literature either in the triple-negative group or in the basal group. However, for inclusion of the mucinous subtype in the basal tumours further studies are required including a larger number of cases for this subtype and confirmation by gene analysis studies.

In the current research, the tumour border was infiltrative (diffusely or focally) in 73.5% of all cases and in 65% of the cases of the basal group; a diffuse pushing border, however, was found in 26.5% of all cases and in 35% of the cases in the basal group. Contrasting findings were reported by Livasy et al. (2006), Rakha et al. (2007), Vincent-Salomon et al. (2007) and Bhargava et al. (2009), who found that triple-negative tumours in general and basal carcinomas in particular are more likely to have a pushing border, which may be attributed to a larger number of medullary and atypical medullary tumours among their study populations. Moreover, many of the cases included in this study had a predominantly pushing border with an infiltrative pattern detected focally; these cases were considered to have an infiltrative border in the current study.

In terms of geographical tumour necrosis, it was found in 73.5% of all cases of this study and in 75% of the basal group cases. These results are in close agreement with those of Livasy et al. (2006), who found it in 74% of cases, and those of Bhargava et al. (2009), who found it in 75% of cases.

Foulkes et al. (2003), Sotiriou et al. (2003) and Fulford et al. (2007) reported that triple-negative tumours and their basal tumour subset have a poor prognosis, and extensive necrosis is a common characteristic of aggressive tumours. This ischaemic tumour necrosis may be attributed to the high expression of the glomeruloid microvascular proliferation factor by these tumours, which promotes neoangiogenesis. The newly formed vascular channels are fragile and may be insufficient to cope with the rapid growth rate of the tumour cells, leading to tumour necrosis (Foulkes et al., 2004).

Central scar formation was reported in 11.8% of the cases in this study and 15% of cases in the basal group. This finding was also reported by Tsuda et al. (1999) to be present in tumours with myoepithelial differentiation. Kreike et al. (2007) also reported this finding in 51% of triple-negative cases. This characteristic might be related to the fibrogenic factors secreted by these tumours.

In terms of tumour architecture, a ribbon-like pattern of growth was found in 11.8% of all cases of this study and 5% of cases of the basal type; this pattern was also reported by Livasy et al. (2006) and Vincent-Salomon et al. (2007). Also, a sheet-like growth pattern was found in 38.2% of cases including 55% of the basal group cases. These results were in agreement with those of Lerma et al. (2007) and Bhargava et al. (2009), who found this pattern in 47 and 21% of cases, respectively.

Variabilities among the results from different studies are probably because of differences in the characteristics of the study population, with more frequent medullary tumours in some of them. Moreover, the prevalence of sheet-like and ribbon-like growth patterns among triple-negative tumours may be related to their expression of P-cadherin, which may enhance cell-to-cell contact (Paredes et al., 2006).

A DCIS was found in 35.3% of the entire population of the current study and 40% of cases in the basal group. The comedo type was found in all cases with an in-situ component. Similarly, Lerma et al. (2007) reported a DCIS component in 45% of the basal group. Bryan et al. (2006) and Livasy et al. (2006) pointed out that the prevalence of high-grade DCIS including comedo type with the basal immunoprofile indicates a precursor probability for the associated invasive component.

In terms of the tumour cell morphology, clear cell change and focal spindle cell morphology were found only in the basal group, accounting for 30 and 15% of the cases, respectively. Clear cell and spindle cell areas could be attributed to myoepithelial differentiation, which was confirmed by S100 positivity.

Rhakha et al. (2006) emphasized that a proportion of basal tumours show a true myoepithelial differentiation. Moreover, Deugnier et al. (2002) pointed out that myoepithelial cells may show a spindle elongated cell morphology, whereas Moinfar (2008) and Rakha et al. (2008) reported spindle cell morphology for metaplastic carcinomas. Moreover, all cases with focal or diffuse squamous differentiation fell into the basal group, representing 30% of basal cases; this differentiation was also reported by Livasy et al. (2006), Moinfar (2008) and Rakha et al. (2008).

In terms of the tumour grade, Korsching et al. (2004), Laakso et al. (2005), Paredes et al. (2006) and Rakha et al. (2008) reported that BBCs are usually high-grade tumours. In the current study, all cases were either grade ‘2’ or grade ‘3’; grade ‘2’ was reported in 79.4% of all cases including 75% of the basal tumours, whereas grade ‘3’ was found in the rest of the cases. The higher tumour grades reported in other studies may be related to the higher percentage of medullary cases included among them.

In the current study, a marked lymphoplasmacytic reaction was observed in 55.9% of all cases and 65% of the basal cases. Similar results were reported by Livasy et al. (2006) and Bhargava et al. (2009), who found this reaction in 56% of cases. A higher percentage was reported by Kreike et al. (2007) (95% of cases) and a lower percentage was reported by Lerma et al. (2007) (49% of cases). The variability observed among different researchers could be attributed to the absence of an agreed consensus for the assessment of such a finding, which would lead to considerable subjectivity in such an assessment.

In terms of the IHC results, as was mentioned earlier in this discussion, identification of the basal immunophenotype was based on the five-marker panel ‘ER negative, PR negative, Her2neu negative, CK5/6 positive and/or EGFR positive’ proposed by Nielsen et al. (2004), who also pointed out that this panel has a specificity of 100% but a sensitivity of only 76% in the identification of basal tumours in comparison with gene analysis studies. According to this panel, the basal tumours accounted for 58.8% of the total study population (triple-negative tumours). This result is in agreement with that of Lerma et al. (2007), who reported that 34–50% of their triple-negative cases were basal. Also, Nielsen et al. (2004) and Kreike et al. (2007) reported that the majority of triple-negative ductal carcinoma were basal. However, Livasy et al. (2006) reported that a basal phenotype was recorded in all triple-negative cases in their study.

Variations in the percentage of basal cases from the triple-negative tumours among the above-mentioned studies and the current one may be because of the different protocols adopted by these studies to define the basal group with the use of variable panels of IHC markers.

In this study, CK5/6-positive staining was detected in 90% of the basal cases, and EGFR-positive staining was similarly observed in 90% of the basal group.

Several studies are in agreement with this one in that the majority of basal tumours are positive for CK5/6 and/or EGFR. Nielsen et al. (2004) detected CK5/6 positivity in 61.9% and EGFR in 57.1% of the basal tumours; moreover, Livasy et al. (2006) reported the same results for CK5/6 and a higher percentage of EGFR expression (72%) of the cases. Moreover, Lerma et al. (2007) reported positive EGFR staining in 30–54% of basal cases. However, Bhargava et al. (2009) detected 71% positive staining results for CK5/6 among basal cases.

In all these studies, basal tumours were defined by a gene analysis study before immunohistochemistry, allowing a wider denominator for assessment, with subsequent lower percentages for each marker.

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Conclusion

From this study, we can conclude that certain morphological characteristics may be commonly found in the triple negative and particularly in the basal variant of invasive breast carcinoma, and these characteristics may be helpful in the identification of the basal variant; however, they are not specific, and therefore, IHC staining for CK5/6 and/or EGFR can be used to confirm the diagnosis in the light of the above-mentioned morphological characteristics.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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