Cytokeratin 5/6 immunohistochemistry assists the differential diagnosis of atypical proliferations of the breast

Otterbach, Friedrich; Bànkfalvi, Àgnes; Bergner, Sonja Verena; Decker, Thomas; Krech, Rainer; Boecker, Werner

doi:10.1046/j.1365-2559.2000.00882.x

Cited by 199 publications

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“…[5][6][7] In addition to routine hematoxylin and eosin-stained sections, various immunohistochemical markers have been used to aid in the distinction between such intraductal epithelial proliferations. Of these, high-molecular weight cytokeratins (CKs) traditionally expressed by the basal epithelial/myoepithelial cells of normal breast, including those detected by the 34bE12 antibody (CK1, CK5, CK10 and CK14) and CK6, have been useful in evaluating both nonpapillary [8][9][10][11] and papillary [12][13][14][15] lesions. In general, these studies have found greater expression of high-molecular weight CKs in usual ductal hyperplasia compared with atypical ductal hyperplasia and ductal carcinoma in-situ, and in intraductal papillomas compared with papillary carcinomas.…”

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confidence: 99%

Luminal cytokeratin expression profiles of breast papillomas and papillary carcinomas and the utility of a cytokeratin 5/p63/cytokeratin 8/18 antibody cocktail in their distinction

et al. 2011

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Luminal cytokeratin (CK) expression in breast papillary lesions, and its potential diagnostic utility among other markers in distinguishing between papillomas and papillary carcinomas, has not been previously evaluated. Such expression was determined in 42 papillary lesions (18 papillary carcinomas and 24 papillomas) by immunostaining with a CK5/p63/CK8/18 antibody cocktail. The mean CK8/18 intensity score and percentage of positive cells were significantly higher in papillary carcinomas (227 and 95%, respectively, vs 86 and 42% in papillomas; both P-values o0.0001), whereas the mean CK5 intensity score and percentage of positive cells were significantly lower (7 and 5%, respectively, vs 107 and 58% in papillomas; both P-values o0.0001). Half (9/18) of the papillary carcinomas expressed p63 vs all (24/24) of the papillomas (P ¼ 0.0001). P63 expression in papillary carcinoma was always (9/9; 100%) focal/limited in nature (expression in o10% of cells), whereas focal expression was seen in only four (17%) papillomas (Po0.0001). Both differential CK (CK8/18 and CK5) expression and p63 were equally sensitive (100%) for the diagnosis of papillary carcinoma, but differential CK expression was more specific (96 vs 83%), resulting in a greater accuracy. However, the best discriminatory power in the distinction from papilloma was achieved when all three markers were used in combination, resulting in 100% sensitivity and specificity values. It is concluded that breast papillary lesions have differential CK expression profiles that, especially in combination with p63, can be useful for their stratification, potentially also in needle biopsy material, in which more accurate and reproducible characterization is needed. Modern Pathology (2011) 24, 185-193; doi:10.1038/modpathol.2010; published online 12 November 2010 Keywords: breast; cytokeratin 5; cytokeratin 8/18; luminal cytokeratin; p63; papillary carcinoma; papilloma By comprising only 1-2% of breast lesions, 1 papillary lesions are relatively rare. Despite that, recognizing that a breast lesion is papillary in nature is not particularly difficult for pathologists. On the other hand, distinguishing between various types of papillary lesions can be problematic. 2,3 Such lesions include intraductal papilloma, intraductal papilloma with atypical ductal hyperplasia, intraductal papilloma with ductal carcinoma in-situ, papillary ductal carcinoma in-situ, intracystic

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confidence: 99%

Luminal cytokeratin expression profiles of breast papillomas and papillary carcinomas and the utility of a cytokeratin 5/p63/cytokeratin 8/18 antibody cocktail in their distinction

et al. 2011

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“…2,8,11,12 Basal phenotype tumors represent a histologically poorly differentiated estrogen receptor (ER)-negative tumor subtype. 4,6,7,9,10,[13][14][15][16] The precise prevalence and clinicopathological characteristics of basal and luminal CK-expressing and -coexpressing tumors remain unclear. In particular, it is currently not known whether amplification of the HER-2 oncogene is characteristic of basal or luminal phenotype tumors, or whether there is no association.…”

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Cytokeratin 5/14-positive breast cancer: true basal phenotype confined to BRCA1 tumors

et al. 2005

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Breast ducts contain two types of epithelial cells, inner luminal cells and outer basal/myoepithelial cells. These cells can be distinguished by their immunophenotype. Cytokeratins (CKs) 8 and 18 are expressed in the luminal layer, whereas CK5/14 and the transcription factor p63 characterize the basal epithelial layer. We studied a population-based cohort of 288 sporadic ductal invasive cancers and found 9% positive for CK5/14 and 4% positive for p63. Using a highly sensitive polymer-based immunohistochemical staining, all sporadic tumors were positive for the luminal CK8/18, including those positive for CK5/14. Pairs of primary tumors and metastases (n ¼ 38) were always concordant for CK5/14 expression. The majority of the CK5/14-positive cases were of histologic grade III (P ¼ 0.0007) and steroid hormone receptor negative (Po0.0001). CK5/14 expression was inversely associated with HER-2 oncogene amplification, but only in the subgroup of estrogen receptornegative tumors (P ¼ 0.007). In a separate set of 42 hereditary breast cancers, the majority (78%) of the BRCA1-associated tumors, but only one of 15 BRCA2-associated tumors was positive for CK5/14. In contrast to sporadic CK5/14-positive tumors, BRCA1-associated tumors displayed less intense CK8/18 staining, including some truly CK5/14-positive CK8/18-negative cases. These results suggest that CK5/14-positive sporadic breast cancers arise from glandularly committed progenitor cells rather than true CK8/18-negative basal cells.

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“…These features are highlighted by the use of high-molecular weight cytokeratins like 34bE12, CK5/6 and CK14. 25,29,30 With the use of this combination of high-and low-molecular weight cytokeratin antibodies along with the H&E slides, we observed significant improvement in the concordance rate among pathologists from fair (0.34 of stage 1) to moderate (0.50 of stage 3). Similar to our study, Douglas-Jones et al 31 have reported an improvement in the diagnostic agreement of core biopsy specimens with the use of immunohistochemistry for CK5/6, calponin and p63.…”

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confidence: 81%

Atypical ductal hyperplasia: interobserver and intraobserver variability

et al. 2011

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Interobserver reproducibility in the diagnosis of benign intraductal proliferative lesions has been poor. The aims of the study were to investigate the inter-and intraobserver variability and the impact of the addition of an immunostain for high-and low-molecular weight keratins on the variability. Nine pathologists reviewed 81 cases of breast proliferative lesions in three stages and assigned each of the lesions to one of the following three diagnoses: usual ductal hyperplasia, atypical ductal hyperplasia and ductal carcinoma in situ. Hematoxylin and eosin slides and corresponding slides stained with ADH-5 cocktail (cytokeratins (CK) 5, 14. 7, 18 and p63) by immunohistochemistry were evaluated. Concordance was evaluated at each stage of the study. The interobserver agreement among the nine pathologists for diagnosing the 81 proliferative breast lesions was fair (j-value ¼ 0.34). The intraobserver j-value ranged from 0.56 to 0.88 (moderate to strong). Complete agreement among nine pathologists was achieved in only nine (11%) cases, at least eight agreed in 20 (25%) cases and seven or more agreed in 38 (47%) cases. Following immunohistochemical stain, a significant improvement in the interobserver concordance (overall j-value ¼ 0.50) was observed (P ¼ 0.015). There was a significant reduction in the total number of atypical ductal hyperplasia diagnosis made by nine pathologists after the use of ADH-5 immunostain. Atypical ductal hyperplasia still remains a diagnostic dilemma with wide variation in both inter-and intraobserver reproducibility among pathologists. The addition of an immunohistochemical stain led to a significant improvement in the concordance rate. More importantly, there was an 8% decrease in the number of lesions classified as atypical ductal hyperplasia in favor of usual hyperplasia; in clinical practice, this could lead to a decrease in the number of surgeries carried out for intraductal proliferative lesions.

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Cytokeratin 5/6 immunohistochemistry assists the differential diagnosis of atypical proliferations of the breast

Abstract: Immunophenotyping of keratin 5/6 expression can be helpful in the diagnosis of atypical hyperplasias and in-situ carcinomas of the breast. It is particularly valuable in the differential diagnosis between benign and atypical proliferative lesions.

Cited by 199 publications

References 30 publications

Luminal cytokeratin expression profiles of breast papillomas and papillary carcinomas and the utility of a cytokeratin 5/p63/cytokeratin 8/18 antibody cocktail in their distinction

Luminal cytokeratin expression profiles of breast papillomas and papillary carcinomas and the utility of a cytokeratin 5/p63/cytokeratin 8/18 antibody cocktail in their distinction

Cytokeratin 5/14-positive breast cancer: true basal phenotype confined to BRCA1 tumors

Atypical ductal hyperplasia: interobserver and intraobserver variability

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