Use of Keratin 34βE12 as an Adjunct in the Diagnosis of Mammary Intraepithelial Neoplasia-Ductal Type—Benign and Malignant Intraductal Proliferations

Moinfar, Farid; Man, Yan Gao; Lininger, Ruth A.; Bodian, Carol; Tavassoli, Fattaneh A.

doi:10.1097/00000478-199909000-00007

Cited by 90 publications

(76 citation statements)

References 28 publications

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“…High molecular weight cytokeratin positivity has been reported as a useful adjunct in differentiating morphologically ambiguous in situ lesions into ductal or lobular categories. 47 However, others have failed to reproduce these findings. Indeed, positive staining seen with the antibody 34betaE12 in lobular neoplasia may in fact be related to the antigen retrieval process.…”

Section: Immunophenotypementioning

confidence: 99%

Lobular neoplasia: morphology, biological potential and management in core biopsies

O’Malley

2010

Modern Pathology

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Lobular neoplasia has been traditionally recognized as a marker of increased risk for subsequent breast carcinoma development; however, molecular studies suggest that it also behaves in a non-obligate precursor manner. We do not know, as yet, how to identify the subgroup of cases that is most likely to progress, but the epidemiological data would indicate that this progression occurs after a long period of time. Thus, the current approach of conservative management of these lesions when identified in excision specimens is justified. Recently, several variants of lobular carcinoma in situ (LCIS), most notably pleomorphic LCIS, have been recognized and these can be difficult to differentiate from ductal carcinoma in situ. Application of strict diagnostic criteria and the judicial use of immunohistochemistry, particularly E-cadherin, can be helpful in this differential diagnosis. Another challenging issue is the management of lobular neoplasia when diagnosed on core biopsy. This controversial issue will be discussed in detail. The goals of this review are (1) to describe the morphological criteria used to diagnose the spectrum of lobular neoplastic lesions, including atypical lobular hyperplasia, LCIS and variants of LCIS; (2) to discuss the data exploring the biological potential of lobular neoplasia from an epidemiological and molecular viewpoint; and (3) to outline the recommendations for management of lobular neoplasia when encountered in core biopsies.

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Section: Immunophenotypementioning

confidence: 99%

Lobular neoplasia: morphology, biological potential and management in core biopsies

O’Malley

2010

Modern Pathology

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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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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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“…We then obtained monoclonal antibodies (MAbs) to an additional 13 keratin proteins to determine if there was a previously unrecognized or undetected crossreaction of 34 ␤ E12 with another keratin protein in formalin-fixed, paraffinembedded tissue. We tested these antibodies against not only the cells of LIN but also the cells of ductal intraepithelial neoplasia (DIN), variants that were shown to be nonreactive with the clone 34 ␤ E12 in our previous (Moinfar et al 1999). If 34 ␤ E12 is crossreacting with another keratin protein, it should be one that is present in the cells of LIN but absent in the cells of higher-grade DIN (ductal carcinoma in situ).…”

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Cytokeratin Immunoreactivity in Lobular Intraepithelial Neoplasia

Bratthauer

Miettinen

Tavassoli³

2003

J Histochem Cytochem.

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S U M M A R Y Eighteen commercially available antibodies reactive against different cytokeratin proteins were tested on classic examples of lobular intraepithelial neoplasia (LIN) and of ductal intraepithelial neoplasia (DIN) of the breast. About 90% of higher-grade DIN (AIDH and DCIS) show no or substantially diminished reaction with clone 34 ␤ E12 (specified as reactive against keratins 1, 5, 10, and 14 as determined by the manufacturer), while the cells of LIN were found to express the antigen reactive with this antibody. To determine which of these four keratins are present in the cells of LIN, antibodies reactive against these individual four keratins were tested. None of the four antibodies to keratins 1, 5, 10, or 14 reacted with the cells of LIN. To investigate this further, 13 additional monoclonal antibodies to various other keratin proteins were tested on the cells of LIN. Those that successfully reacted with the cells of LIN were further tested on the cells of DIN. All of the individual antibodies reactive with the cells of LIN were also reactive with the cells of DIN to a degree, with clone RCK108 (reactive against keratin 19) coming the closest to demonstrating the reactivity seen with 34 ␤ E12. We conclude that the reactivity seen in the cells of LIN with 34 ␤ E12 is due to either (a) a crossreaction with keratin 19 that is slightly less prominent than the reaction of the individual clone RCK108, (b) a crossreaction with a keratin protein that was not tested (3, 11, 12), (c) a crossreaction with a protein closely resembling keratin in formalin-fixed, paraffin-embedded tissue, or (d) the detection of a mutated or truncated form of keratin 1, 5, 10, or 14 that cannot be detected by the individual monoclonal antibody. L obular intraepithelial neoplasia (LIN) is a disease of the breast that increases the risk for breast cancer in those afflicted (Tavassoli 1999). LIN cells are usually characterized by a lack of E-cadherin protein along with the presence of a high molecular weight cytokeratin as demonstrated by immunohistochemistry (IHC) with the commonly used antibody clone 34 ␤ E12 (Bratthauer et al. 2002). Available worldwide and in use for 20 years, clone 34 ␤ E12 is believed to be reactive against keratin proteins 1, 5, 10, and 14, according to the manufacturer (Gown and Vogel 1982). This antibody shows a perinuclear, often polarized immunoreactivity in every LIN we have evaluated, 40 of which have been reported on (Bratthauer et al. 2002) and in an additional 20 cases studied since.This study was designed to determine which of the four keratin proteins identified by 34 ␤ E12 were detected in the cells of LIN.To that end, we tested individual antibodies reactive against keratins 1, 5, 10, and 14 on classic LIN. To our surprise, none of these reacted with the cells of LIN. We then obtained monoclonal antibodies (MAbs) to an additional 13 keratin proteins to determine if there was a previously unrecognized or undetected crossreaction of 34 ␤ E12 with another keratin protein in formalin-fixed, paraff...

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Use of Keratin 34βE12 as an Adjunct in the Diagnosis of Mammary Intraepithelial Neoplasia-Ductal Type—Benign and Malignant Intraductal Proliferations

Cited by 90 publications

References 28 publications

Lobular neoplasia: morphology, biological potential and management in core biopsies

Lobular neoplasia: morphology, biological potential and management in core biopsies

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 Immunoreactivity in Lobular Intraepithelial Neoplasia

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