Immunohistochemical characterization of molecular subtypes of invasive breast cancer: a study from North India

In recent years breast cancer has been classified on the basis of its molecular characteristics by gene expression profiling. A similar classification using immunohistochemistry has been identified so that it has a wider application. This study was designed to define the precise prevalence of molecular subtypes of invasive breast carcinoma using immunohistochemistry in patients from north India and to correlate it with known clinical and histological prognostic factors. Based on ER/PR/Her2/neu expression, 100 cases of invasive breast cancer were categorized into: ER+ and ? or PR+ and Her2/neu? (47%), ER+ and?or PR+ and Her2/neu+ (15%), ER? and ? or PR? and Her2/neu+ (Her2/neu overexpressing, 21%), ER?, PR? and Her2/neu? (Triple negative, 17%). All cases demonstrated positivity for the luminal Cytokeratins 8/18. In addition, 10% of these tumours showed expression of the basal markers (CK4/14, CK5/6). Among the 17 triple negative cases, eight cases were positive for one of the basal markers and two cases with basal marker expression were Her2/neu overexpressing. The basal markers showed significant correlations only with histological grade and ER negative status. On the basis of hormone receptor, Her‐2/neu and cytokeratin expressions, distinct subclasses of breast cancer have been identified which show significant differences in relation to histological grade and ER status. Expression of basal markers is needed to define basal‐like breast cancer.     

P-cadherin and cytokeratin 5: useful adjunct markers to distinguish basal-like ductal carcinomas in situ

Gene expression profiles of invasive breast carcinomas have identified a subgroup of tumours with worse prognosis, which have been called "basal-like". These are characterized by a specific pattern of expression, being estrogen receptor (ER) and HER2 negative, and frequently expressing at least one basal marker such as basal cytokeratins or epidermal growth factor receptor (EGFR). Previously, our group characterized basal-like tumours in a series of invasive breast carcinomas using P-cadherin (P-CD), p63 and cytokeratin 5 (CK5). Based on that study, we hypothesized that those high-grade basal-like invasive carcinomas might have a pre-invasive counterpart, which could be identified using the same approach. A series of 79 ductal carcinomas in situ (DCIS) were classified into distinct subgroups according to their ER, HER2 and basal markers expression. Luminal DCIS expressed ER and constituted 64.6% of the series; the HER2 overexpressing tumours did not express ER and represented 25.3% of the cases, whereas 10.1% lack the expression of ER and HER2 and expressed at least one basal marker (P-CD, CK5, CK14, p63, vimentin and/or EGFR). These basal-like DCIS were mostly high-grade, with comedo-type necrosis, and consistently showed expression of P-CD and CK5. In conclusion, DCIS with a basal-like phenotype represent a small percentage in our series, being P-CD and CK5, the most useful adjunct markers to distinguish this subset of carcinomas in situ of the breast.     

Cytokeratin profiles of male breast cancers

AIMS: The prognostic factors and expression of molecular markers in male breast carcinomas are similar to those in female breast cancers. The identification of distinct cytokeratin (CK) profiles (basal as opposed to luminal cells) helps to identify subsets of tumours with different clinical behaviour. The aim of this study was to investigate CK expression in male breast cancer. METHODS AND RESULTS: Thirty-two cases of male breast cancer were studied. The panel of CKs studied by immunohistochemistry included: 5/6, 14, 17, 18 and 19. Pathological findings and CK expression were analysed in all cases. Histological patterns included ductal carcinoma in situ, invasive ductal carcinoma and mixed patterns. Four cases were positive for CK5/6 and CK14, identifying a basal-like phenotype. CK17 was negative in all but two cases. All cases expressing either CK5/6 or CK14 were invasive carcinomas of high nuclear and histological grade and were also larger compared with the tumours not expressing CK5/6 and CK14. All tumours except three (also negative for CK5/6) expressed CK18 and CK19. The four basal-like tumours were negative for Her-2 expression. CONCLUSIONS: Male breast carcinomas have a basal-like phenotype that is similar in frequency to that of female breast carcinomas. The expression of CK5/6 and CK14 identifies a subset of pathologically aggressive male breast cancers.     

Molecular classification predicts survival for breast cancer patients in Vietnam: a single institutional retrospective analysis

Background: The Bhagarva surrogate molecular subtype definitions classify invasive breast cancer into seven the different subgroups based on immunohistochemical (IHC) criteria according to expression levels of markers as ER, PR, HER2, EGFR and/or basal cytokeratin (CK5/6) which are different in prognosis and responsiveness to adjuvant therapy. Purpose: The present study aimed to classify primary breast cancers and directly compares the prognostic significance of the intrinsic subtypes. Methods: The current study was conducted on 522 breast cancer patients who had surgery, but had not received neoadjuvant chemotherapy, from 2011 to 2014. The clinicopathologic characteristics were recorded. IHC staining was performed for ER, PR, HER2, Ki67, CK5/6, EGFR and D2-40 markers. All breast cancer patients were stratified according to Bhagarva criteria. The followed-up patients’ survival was analyzed by using Kaplan-Meier and Log-Rank models. Results: The luminal A (LUMA) was observed at the highest rate (32.5%). Non-basal-like triple negative phenotype (TNB-) and Luminal A HER2-Hybrid (LAHH) were the least common (3.3% in both). LUMA and luminal B (LUMB) were significantly associated with better prognostic features compared to HER2, basal-like triple negative phenotype (TNB+) and TNB-. Statistically significant differences were demonstrated between overall survival (OS), disease-free survival (DFS) and molecular subtypes (P<0.05), of which LUMB and LUMA had the highest rate of OS and DFS being 97.2 and 93.7%; and 97.2 and 90.5%, respectively. Conversely, HER2 revealed the worst prognosis with the lowest prevalence of OS and DFS (72.5 and 69.9%, respectively). Conclusion: The molecular subtypes had a distinct OS and DFS. The intrinsic stratification displayed inversely to clinicopathological features in breast cancer.     

Prognostic stratification of muscle invasive urothelial carcinomas using limited immunohistochemical panel of Gata3 and cytokeratins 5/6, 14 and 20

BackgroundGenomic studies have delineated distinct molecular subgroups of urothelial carcinomas whose prognostic impact extends beyond traditional stage and grade groupings. The ‘basal’ subgroup shows increased gene expression levels of KRT5, KRT6, and KRT14 and low expression levels of GATA binding protein 3, and is associated with an extremely poor outcome. Identification of this subset is necessary for improved patient management and research on targeted therapies. We aimed to assess the prognostic utility of immunohistochemistry (IHC) for basal markers: cytokeratin 5/6 (CK5/6) and 14 (CK14), and luminal markers: cytokeratin 20 (CK20) and Gata3 in muscle invasive urothelial carcinomas (MIBC).Materials and methodsStudy was of retrospective design (2014‐2017). All chemotherapy naïve patients of MIBC undergoing radical cystectomy were included. IHC was performed on formalin fixed paraffin-embedded whole tumor sections.ResultsAmong 40 cases of MIBC included, 45% (18/40) were positive for one or both basal markers, 37.5% (15/40) were positive for one or both luminal markers, while 15% (6/40) were positive for both basal and luminal markers. One case did not express any of the four markers. MIBCs expressing only basal markers presented at an advanced stage with frequent squamous differentiation and showed a trend towards shorter overall survival. Gata3+ MIBCs showed the best outcome irrespective of expression of other markers, while CK14+/Gata3- MIBCs were associated with worst outcomes. Gata3-/CK14- MIBCs showed intermediate survival outcomes. CK5/6, CK20 and p53 expression did not significantly correlate with outcome.ConclusionIHC for Gata-3 and CK14 stratified MIBC into distinct prognostic subsets.     

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

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.     

Salivary duct carcinomas can be classified into luminal androgen receptor‐positive,HER2 and basal‐like phenotypes*

Di Palma S, Simpson R H W, Marchiò C, Skálová A, Ungari M, Sandison A, Whitaker S, Parry S & Reis‐Filho J S
(2012) Histopathology  61, 629–643 Salivary duct carcinomas can be classified into luminal androgen receptor‐positive, HER2 and basal‐like phenotypes Aims: The aim of this study was to devise a molecular classification for salivary duct carcinomas (SDCs) based on the similarities between SDCs and breast carcinomas and on characteristics of the microarray‐based gene expression profiling‐defined molecular subtypes of breast cancer. Methods and results: Forty‐two pure salivary duct carcinomas, 35 of which contained an in‐situ component as defined by histological review and/or immunohistochemical analysis, were stained with antibodies for oestrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and cytokeratin (CK) 5/6. Based on these markers, tumours were classified into HER2, luminal androgen receptor‐positive, basal‐like, luminal and indeterminate phenotype. Analysis revealed that 16.7%, 69%, 4.8%, 9.5% and 0% were of HER2, luminal androgen receptor‐positive, basal‐like, indeterminate and luminal phenotype, respectively. The in‐situ and invasive components displayed the same molecular subtype in all but one case. Conclusions: Salivary duct carcinomas can be classified into molecular subgroups approximately equivalent to those in the breast. We also report on the existence of a subgroup of bona fide pure salivary duct carcinomas that have a ‘basal‐like’ phenotype. Understanding the phenotypic complexity of SDCs may help to expedite the identification of novel therapeutic targets for these aggressive tumours.     

Independent prognostic value of the basal-like phenotype of breast cancer and associations with EGFR and candidate stem cell marker BMI-1

Aims:  To study the relationship between basal-like breast cancers, epidermal growth factor receptor (EGFR) and candidate stem cell markers (BMI-1, EZH2, Oct-4) in a population-based setting.
Methods and results:  Immunohistochemistry was evaluated in a series of 190 breast cancers. Basal-like phenotype (BLP) 1–5 was found in 4.3–14.3% of cases. EGFR was expressed in 9% of cases and associated with cytokeratin (CK) 5 and P-cadherin positivity, but not with survival; 28% of CK5+ cases were EGFR+. On multivariate analysis, basal-like differentiation and lymph node status were independent prognostic factors of comparable strength. BMI-1 positivity (42.6%) was associated with absence of basal-like features, oestrogen receptor positivity and low Ki67, but not related to survival. BMI was not associated with EZH2 expression, and these markers tended to show opposite associations with other variables, suggesting different roles in breast cancer. Oct-4 expression was not detected in this series.
Conclusions:  Basal-like features and lymph node status were strong and independent prognostic factors in this population-based series of breast cancer. Neither EGFR nor BMI-1 had significant prognostic impact, whereas EZH2 expression was associated with decreased survival. BMI-1 was inversely related to basal-like factors, and a stem cell phenotype of the basal-like subgroup could not be verified by this marker.     

p63, cytokeratin 5, and P-cadherin: three molecular markers to distinguish basal phenotype in breast carcinomas

Human breast carcinomas represent a heterogeneous group of tumors diverse in behavior, outcome, and response to therapy. However, the current system of pathological classification does not take into account biologic determinants of prognosis. The purpose of this study was to classify and characterize breast carcinomas based on variations in protein expression patterns derived from immunohistochemical analyses on tissue microarrays (TMAs). Therefore, 11 TMAs representing 168 invasive breast carcinomas were constructed. Breast tumors were classified into four different subtypes depending on estrogen receptor (ER) and HER2 expression. Basal-type tumors expressed neither of these proteins and represented 7.6% of our series; basal-like HER2-overexpressing tumors did not express ER and represented 17.7%; luminal-type tumors expressed ER and represented 72.8% of this series (luminal A 56.3%, luminal B 16.5%). Moreover, we characterized each subtype based on P-cadherin (P-CD), p63, cytokeratin (CK)5, BCL2, and Ki67 expression. Basal-type tumors were mostly grade III, more frequently P-CD-, p63-, and CK5-positive, and had a high proliferation rate. Conversely, luminal-type tumors rarely expressed basal markers and had a low grade and proliferation rate. Basal-like HER2-overexpressing tumors showed a basal-type profile similar with a high grade and up-regulation of P-CD and CK5. With this study, we show that P-CD, p63, and CK5 are important molecular markers that can be used to distinguish a basal phenotype. In addition, we also demonstrate the usefulness of TMAs in breast carcinoma immunoprofiling.     

Relationship between nuclear grade of ductal carcinoma in situ and cell origin markers

Ductal carcinoma in situ (DCIS) is a group of heterogeneous lesions genetically, morphologically, and biologically. Recently, breast epithelium in the terminal ductal lobular unit has been sub-classified based on the expression of several cytokeratin markers as stem cells (CK5/6 +), luminal cells (CK8, CK18 +), and basal cells (CK14, CK17 +). In this study we describe the relationship between DCIS of different nuclear grades (non-high grade and high grade) and these cell origin markers. Fifty-three cases of non-high grade and 46 cases of high grade DCIS were selected, and representative sections from each case were stained with antibodies to these cytokeratin markers. High grade DCIS showed significantly higher rates of expression with stem and basal cell markers compared with non-high grade DCIS (p <0.05). The majority of DCIS, both high grade and non-high grade, expressed luminal cell markers (67% to 91%) and single type of cell origin marker (72% to 87%). High-grade DCIS more frequently co-expressed all three types of cell origin markers compared with non-high grade DCIS (p <0.05). In summary, a subset of high grade DCIS frequently rises from stem or/and basal cell populations; the subset is associated with poor prognosis in invasive breast carcinoma. Thus, these markers may be used to identify a potentially more aggressive subgroup of breast carcinoma at its pre-invasive stage (DCIS), and to manage it accordingly. Second, most DCIS express luminal cell markers, suggesting that malignant transformation occurs relatively late along the cell differentiation pathway, contrary to the traditional belief that most neoplasms arise from a more primitive stem cell population. Third, the majority of DCIS exclusively express one type of progenitor marker, indicating that in most incidences they may arise from a single progenitor population. Last, triple expression of all types of cell origin marker is frequently associated with high grade DCIS, suggesting that more complicated pathways are involved in these more aggressive lesions. Further studies are needed to delineate the relationships of cell origin markers in DCIS and invasive carcinoma to the clinical outcome.     

Breast cancer in the elderly: a histological assessment

Aims:  To understand the correlation between the expression status of different biological markers in breast cancers in the elderly.
Methods and results:  Three hundred and ninety-seven cases were evaluated for expression of hormone receptors [oestrogen receptors (ER) α and β, progesterone receptor (PR)], basal markers [p63, cytokeratin (CK) 5/6 and CK14] and others (HER2/neu, synaptophysin and chromogranin). The expression rates were 60, 29, 25, 6, 14, 8, 28, 17 and 5%, respectively, for these markers. The expression of ER α and β, PR, synaptophysin and chromogranin at any level correlated with low nuclear or tumour grades, whereas the expression of HER2/neu, CK5/6 and CK14 at any level correlated with high nuclear grade. By using hierarchical clustering, groups of HER2, luminal and basal types were identified. In addition, a neuroendocrine group was also identified, being characterized by expression of synaptophysin, chromogranin, ER and PR, but not HER2/neu, and other basal cytokeratins. This group was associated with lower nuclear grade, and hence better prognosis.
Conclusions:  Breast cancer in the elderly shows similar molecular groupings as other breast cancers, with an additional neuroendocrine group that is associated with a favourable biological marker profile.     

Centrally necrotizing carcinoma of the breast: clinicopathological analysis of 33 cases indicating its basal‐like phenotype and poor prognosis

Yu L, Yang W, Cai X, Shi D, Fan Y & Lu H
(2010) Histopathology 57 , 193–201 Centrally necrotizing carcinoma of the breast: clinicopathological analysis of 33 cases indicating its basal‐like phenotype and poor prognosis Aims: To investigate the clinicopathological features and immunophenotype of centrally necrotizing carcinoma (CNC) of the breast to ascertain its relationship to basal‐like phenotype and its prognosis. Methods and results: The clinical and pathological characteristics of 33 CNCs were reviewed. Immunohis‐tochemical study of oestrogen receptor, progesterone receptor, HER2, cytokeratin (CK) 8/18, high‐molecular‐weight CK (34βE12), CK5/6, CK14, CK17, smooth muscle antigen, p63, vimentin and epidermal growth factor receptor was performed. The striking feature of CNC was a central, necrotic or acellular zone surrounded by a ring‐like area of viable tumour cells. The central zone showed three morphological types: predominance of coagulative necrosis (21 cases), predominance of fibrosis and scar tissue (nine cases) and infarction (three cases). Tumour cells displayed invasive ductal carcinoma of high grade. The expression rate of basal‐like markers was higher than that of myoepithelial markers (87.9% versus 46.2%). Basal‐like subtype was shown by 63.6% of cases. The expression rate of CK5/6 (90.5%) was highest among basal‐like markers. Follow‐up data of 19 patients were available. Median progression‐free survival was 15.5 months. In 12 patients (63.2%), local recurrence and/or distant metastasis developed (median time to recurrence and/or metastasis, 14.0 months). Conclusions: CNC has distinctive morphological features, which mostly exhibit a basal‐like immunophenotype and poor prognosis. CNC is a typical representative of basal‐like breast cancer.     

Mesothelial markers in high-grade breast carcinoma

Duhig E E, Kalpakos L, Yang I A & Clarke B E
(2011) Histopathology 59 , 957–964 Mesothelial markers in high‐grade breast carcinoma Aims: Advances in molecular profiling have subdivided breast carcinomas into distinct subtypes. Basal carcinomas are generally oestrogen receptor (ER)?progesterone receptor (PR)?/human epidermal growth factor receptor 2 (HER2)?, and cytokeratin (CK)5/6+. This profile overlaps with that of mesothelial cells. This study of high‐grade breast carcinomas was undertaken to determine the expression of mesothelial markers. Methods and results: Immunohistochemistry was performed on 23 basal‐like breast carcinomas and 30 high‐grade breast carcinomas with variable ER, PR and HER2 expression. The incidence of staining of CK5/6, CK14, calretinin, Wilms’ tumour 1 (WT1), thrombomodulin and epithelial membrane antigen was assessed statistically. CK14 staining was more specifically associated with triple‐negative tumours than CK5/6. Calretinin positivity was statistically associated with basal‐like carcinomas. WT1 and thrombomodulin expression was infrequent and limited to a small number of non‐basal carcinomas. Conclusions: There is an overlap between the immunophenotype of mesothelial cells and that of basal‐like carcinomas of breast. Positive calretinin and CK5/6 are not specific, and may be seen in both mesothelial cells and basal‐like breast carcinomas. Negative ER and PR of basal carcinomas may also bias the observer against a breast origin. However, other negative mesothelial markers, such as WT1 and thrombomodulin, may help point to the correct diagnosis.     

Vimentin and laminin expression is associated with basal-like phenotype in both sporadic and BRCA1-associated breast carcinomas

AIMS: To determine whether basal-like phenotype and vimentin and/or laminin are related in both sporadic/familial (BRCA1 or BRCA2 mutated) tumours. METHODS: 230 non-familial and 28 hereditary node-negative invasive breast carcinomas were immunohistochemically analysed for oestrogen receptors (ER), progesterone receptors (PR), cytokeratin 5/6 (CK5/6), epidermal growth factor receptors (EGFR), Ki67, p53, vimentin and laminin, using tissue microarrays. Tumours were considered to have basal-like phenotype if they were ER negative and HER2 negative, but positive for CK5/6 and/or EGFR. RESULTS: In sporadic tumours, vimentin expression was found in 77.8% cases with basal-like phenotype and 15.5% of non-basal cases (p<0.001). In familial cases, vimentin was expressed in 83.3% basal-like cancers and 16.7% of non-basal tumours (p<0.001). Vimentin expression was more frequent in BRCA1 than BRCA2 mutation carriers. Vimentin expressing tumours were associated with poor prognosis (p = 0.012) among patients not receiving adjuvant chemotherapy and showed a trend for local recurrence or visceral but not bone metastasis (p = 0.021). Laminin expression was also related to basal-like phenotype in both sporadic/familial cases (p<0.001 and p = 0.007, respectively), but neither with prognosis nor recurrence pattern in sporadic cancers. CONCLUSIONS: Vimentin and laminin expression is associated with basal-like phenotype in breast cancer. Expression of vimentin and laminin is characteristic of BRCA1 associated tumours. Since vimentin and laminin staining is widely used by pathologists for diagnostic purposes, thus demonstrating the robustness of their specific antibodies, the immunohistochemical evaluation of these two molecules could be used in identification of basal-like breast tumours in both sporadic/familial cases.     

The combination of high cyclin E and Skp2 expression in breast cancer is associated with a poor prognosis and the basal phenotype

Gene expression studies have identified a basal phenotype of breast cancer; these are hormone receptor and HER2-negative cancers with poor prognosis. High levels of cyclin E and Skp2, and low levels of p27 have previously been individually associated with both basal-like breast cancer and a poor outcome after diagnosis. The goal of this study was to first confirm the prognostic value of these biomolecular markers using a breast cancer tissue microarray. Second, we also test the hypothesis that the combined phenotype of high cyclin E, low p27, and high Skp2 would be a strong predictor of outcome and would be closely associated with the basal phenotype of breast cancer. Our cohort consisted of 438 cases of breast cancer and the median follow-up was 15.4 years. The tissue microarray was constructed from archival tumor blocks and we used commercially available antibodies for biomarker immunostaining. Cyclin E was positive in 46% of cases, p27 was negative in 62%, and Skp2 was positive in 35%. We found cyclin E and Skp2 to be prognostic for breast cancer-specific survival in univariate analyses, but p27 was not prognostic. The strongest predictor of outcome was the combination of cyclin E positive and Skp2 positive (difference in survival of 19% at 10 years, P = .0009). This combination was present in 78 (27%) of 288 cases for which data on both biomarkers were available. This combination was also highly associated with young age at diagnosis, grade 3 tumors, ER-negative status, HER2-negative status, and the basal biomarkers epidermal growth factor receptor and cytokeratin 5/6. However, in a multivariate model including standard clinicopathologic variables, this combination was not found to have independent prognostic significance. In conclusion, the combination of high cyclin E and Skp2 expression predicts for poor prognosis in breast cancer in univariate analysis only, it is associated with high risk features, and it is associated with the basal phenotype.     

乳腺浸润性导管癌分子亚型与临床病理特征及预后的关系

目的 检测乳腺浸润性导管癌的临床病理特征及特定蛋白的表达情况,对其进行分型,探讨各哑型与预后的关系.方法 采用免疫组织化学EnVision法检测128例浸润性导管癌ER、PR、HER2和CK5/6的表达,参考文献报道的免疫分型方法 对其分型,并对HER2过表达型9例进行FISH检测.结果 ER、PR、HER2和CKS/6在本组128例浸润性导管癌中的阳性表达率分别为67%(86/128)、45%(58/128)、27%(34/128)和27%(34/128),并将128例分为5种免疫哑型,管腔A型55%(70/128),管腔B型20%(25/128),HER2过表达型7%(9/128),基底细胞样型10%(13/128),无法分类型8%(11/128).FISH检测HER2过表达型9例均为HER2基因扩增.各分子亚型间预后差异具有统计学意义,管腔A型预后最好,基底细胞型预后较差.多因素分析,乳腺癌临床分期和免疫分型是独立的预后因素.月经状态在乳腺癌各免疫亚型中的分布差异有统计学意义.结论 通过检测ER、PR、HER2和CK5/6的表达可以将乳腺浸润性导管癌分成具有不同生物学行为的5个免疫亚型,对于评估预后,指导治疗具有一定的意义.     

乳腺浸润性导管癌分子亚型与临床病理特征及预后的关系

目的 检测乳腺浸润性导管癌的临床病理特征及特定蛋白的表达情况,对其进行分型,探讨各哑型与预后的关系.方法 采用免疫组织化学EnVision法检测128例浸润性导管癌ER、PR、HER2和CK5/6的表达,参考文献报道的免疫分型方法 对其分型,并对HER2过表达型9例进行FISH检测.结果 ER、PR、HER2和CKS/6在本组128例浸润性导管癌中的阳性表达率分别为67%(86/128)、45%(58/128)、27%(34/128)和27%(34/128),并将128例分为5种免疫哑型,管腔A型55%(70/128),管腔B型20%(25/128),HER2过表达型7%(9/128),基底细胞样型10%(13/128),无法分类型8%(11/128).FISH检测HER2过表达型9例均为HER2基因扩增.各分子亚型间预后差异具有统计学意义,管腔A型预后最好,基底细胞型预后较差.多因素分析,乳腺癌临床分期和免疫分型是独立的预后因素.月经状态在乳腺癌各免疫亚型中的分布差异有统计学意义.结论 通过检测ER、PR、HER2和CK5/6的表达可以将乳腺浸润性导管癌分成具有不同生物学行为的5个免疫亚型,对于评估预后,指导治疗具有一定的意义.     

乳腺浸润性导管癌分子亚型与临床病理特征及预后的关系

目的 检测乳腺浸润性导管癌的临床病理特征及特定蛋白的表达情况,对其进行分型,探讨各哑型与预后的关系.方法 采用免疫组织化学EnVision法检测128例浸润性导管癌ER、PR、HER2和CK5/6的表达,参考文献报道的免疫分型方法 对其分型,并对HER2过表达型9例进行FISH检测.结果 ER、PR、HER2和CKS/6在本组128例浸润性导管癌中的阳性表达率分别为67%(86/128)、45%(58/128)、27%(34/128)和27%(34/128),并将128例分为5种免疫哑型,管腔A型55%(70/128),管腔B型20%(25/128),HER2过表达型7%(9/128),基底细胞样型10%(13/128),无法分类型8%(11/128).FISH检测HER2过表达型9例均为HER2基因扩增.各分子亚型间预后差异具有统计学意义,管腔A型预后最好,基底细胞型预后较差.多因素分析,乳腺癌临床分期和免疫分型是独立的预后因素.月经状态在乳腺癌各免疫亚型中的分布差异有统计学意义.结论 通过检测ER、PR、HER2和CK5/6的表达可以将乳腺浸润性导管癌分成具有不同生物学行为的5个免疫亚型,对于评估预后,指导治疗具有一定的意义.     

Coordinated expression of ER, PR and HER2 define different prognostic subtypes among poorly differentiated breast carcinomas

Aims:  Histological grade is one of the most important prognostic factors in breast carcinomas, but poorly differentiated neoplasms still have quite heterogeneous biological behaviour, since they can be genetically classified as basal-like, HER2+ or even luminal. The aim was to analyse the frequency of oestrogen receptor (ER), progesterone receptor (PR) and HER2 expression profiles among breast carcinomas with <10% tubular formation, and their correlation with classic prognostic factors.
Methods and results:  One hundred and thirty-four samples of paraffin-embedded tumours were studied retrospectively. The tumours were classified in to four groups by their ER/PR/HER2 profile: (i) ER+ and/or PR+ but HER2−; (ii) ER+ and/or PR+ and HER2+; (iii) ER− and/or PR− but HER2+; and (iv) ER−, PR− and HER2− (triple-negative). The histological features of triple-negative and HER2+ carcinomas overlap. The only difference was the expression of basal cytokeratins (basal CK), which was more frequent among triple-negative carcinomas. Basal-CK expression defined a more aggressive group of tumours, according to the pathological features, regardless of the immunohistochemical profile.
Conclusions:  Group 1 and 2 tumours (ER+ and/or PR+ tumours with or without HER2 expression) were not statistically different, suggesting that poorly differentiated carcinomas with hormone receptors correspond to the luminal B type of tumour. Among poorly differentiated breast carcinomas, the classic profile associated with basal-CK identifies distinct subtypes equivalent to those seen by genetic classification.     

Molecular classifications of breast carcinoma with similar terminology and different definitions: are they the same?

There are 4 major molecular classifications in the literature that divide breast carcinoma into basal and nonbasal subtypes, with basal subtypes associated with poor prognosis. Basal subtype is defined as positive for cytokeratin (CK) 5/6, CK14, and/or CK17 in CK classification; negative for ER, PR, and HER2 in triple negative (TN) classification; negative for ER and negative or positive for HER2 in ER/HER2 classification; and positive for CK5/6, CK14, CK17, and/or EGFR; and negative for ER, PR, and HER2 in CK/TN classification. These classifications use similar terminology but different definitions; it is critical to understand the precise relationship between them. We compared these 4 classifications in 195 breast carcinomas and found that (1) the rates of basal subtypes varied from 5% to 36% for ductal carcinoma in situ and 14% to 40% for invasive ductal carcinoma. (2) The rates of basal subtypes varied from 19% to 76% for HG carcinoma and 1% to 7% for NHG carcinoma. (3) The rates of basal subtypes were strongly associated with tumor grades (P < .001) in all classifications and associated with tumor types (in situ versus invasive ductal carcinomas) in TN (P < .001) and CK/TN classifications (P = .035). (4) These classifications were related but not interchangeable (kappa ranges from 0.140 to 0.658 for HG carcinoma and from 0.098 to 0.654 for NHG carcinoma). In conclusion, although these classifications all divide breast carcinoma into basal and nonbasal subtypes, they are not interchangeable. More studies are needed to evaluate to their values in predicting prognosis and guiding individualized therapy.