Morphologic and Molecular Evolutionary Pathways of Low Nuclear Grade Invasive Breast Cancers and Their Putative Precursor Lesions: Further Evidence to Support the Concept of Low Nuclear Grade Breast Neoplasia Family

Abdel-Fatah, Tarek M.; Powe, Desmond G.; Hodi, Zsolt; Reis‐Filho, Jorge S.; Lee, Andrew H.S.; Ellis, Ian O.

doi:10.1097/pas.0b013e318161d1a5

Cited by 218 publications

(147 citation statements)

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“…Although not specifically addressed in this study, this combination may also be useful to better distinguish between papillomas secondarily involved by usual ductal hyperplasia and those secondarily involved by atypical ductal hyperplasia and/or ductal carcinoma in-situ, in a manner similar to their utility in discriminating between nonpapillary intraductal epithelial proliferations. 8,16,17 Another argument for using CK8/18 in the evaluation of papillary lesions is that its inclusion can provide a 'positive reaction' to support a diagnosis of malignancy (papillary carcinoma), instead of just a negative reaction that might be obtained with only CK5 (and/or p63). Of note, this latter rationale has been used to argue (successfully) for using amethylacyl-CoA racemase in the evaluation of atypical foci in prostate needle biopsy material, a widely accepted practice in contemporary surgical pathology.…”

Section: Discussionmentioning

confidence: 99%

“…8,16,17 Such expression, combined with decreased/absent high-molecular weight CK expression, has been used to further help distinguish atypical ductal hyperplasia and ductal carcinoma in-situ from usual ductal hyperplasia. There are, however, no studies that systematically evaluate the expression of such low-molecular weight CKs in papillary lesions of the breast.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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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“…4 Recently, Abdel-Fatah et al proposed a ''low-grade mammary neoplasia family'' hypothesis that includes columnar cell lesions as a precursor lesion. 5 This hypothesis is based on molecular linkage analyses available in the literature, as well as a comprehensive morphologic study comparing the association of different putative precursor lesions and the development of some special types of low-grade invasive mammary carcinoma. These analyses were based on columnar cell lesions coexisting with more advanced lesions in the same specimen.…”

Section: Introductionmentioning

confidence: 99%

Clinicopathologic characteristics of carcinomas that develop after a biopsy containing columnar cell lesions

Boulos

Dupont

Schuyler

et al. 2011

Cancer

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BACKGROUND: Columnar cell lesions are frequently associated with atypical ductal hyperplasia, lobular neoplasia, and tubular carcinoma, and have been suggested as a precursor lesion for low-grade carcinomas. However, in longterm follow-up studies, columnar cell lesions are associated with only a slight increase in later breast cancer development. If columnar cell lesions are precursor lesions, one would expect subsequent cancers to develop at the same site as the biopsy and to be preferentially of low grade. The goal of this article is to review the clinical and pathologic features of carcinomas that develop after a diagnosis of columnar cell lesion to try to establish whether these lesions are precursors to low-grade invasive carcinoma. METHODS: The authors reviewed biopsies containing columnar cell lesions, using the criteria of Schnitt and Vincent-Salomon, from 77 women in the Nashville Breast Cohort who developed subsequent breast carcinoma. Clinicopathologic features including laterality, type, and grade of the subsequent cancer were recorded. RESULTS: Breast cancer developed a median of 11 years after initial biopsy. The median age at diagnosis was 60 years. The majority of invasive carcinomas were of no special type and of intermediate grade. Moreover, the carcinomas were as likely to occur in the contralateral breast as in the breast that was originally diagnosed with columnar cell lesion, regardless of columnar cell lesion subtype (P ¼ .48). CONCLUSIONS: Carcinoma subsequent to columnar cell lesions may occur in either breast and tends to show a similar grade and type distribution as sporadic breast cancer. These findings argue against columnar cell lesions being a true precursor for lowgrade invasive carcinoma.

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“…18 Molecular studies have shown similar genetic alterations in flat epithelial atypia, atypical hyperplasia, and low-grade carcinoma in the same tissue section, suggesting that flat epithelial atypia may be a non-obligate precursor in a low-grade breast neoplasia pathway. 19,20 In long-term follow-up studies of open biopsies, the risk associated with columnar cell lesions and flat epithelial atypia alone appears to be lower than the risk associated with atypical ductal or atypical lobular hyperplasia. 16,17 In a prior series from our institution, we reported a series of 31 cases from 1998 to 2003, with available follow-up excisions, 4 (12.9%) of which contained carcinoma.…”

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confidence: 99%

Management of flat epithelial atypia on breast core biopsy may be individualized based on correlation with imaging studies

et al. 2015

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Flat epithelial atypia of the breast commonly co-exists with atypical ductal hyperplasia, lobular neoplasia, and indolent forms of invasive carcinomas such as tubular carcinoma. Most patients with pure flat epithelial atypia on core biopsy undergo surgical excision to evaluate for carcinoma in the adjacent breast tissue. Studies to date have reported varying upgrade rates with most recommending follow-up excision. These studies have often lacked detailed radiographic correlation, central review by breast pathologists and information regarding the biology of the carcinomas identified upon excision. In this study, we report the frequency of upgrade to invasive carcinoma or ductal carcinoma in situ in excision specimens following a diagnosis of pure flat epithelial atypia on core biopsy. Radiographic correlation is performed for each case and grade/receptor status of detected carcinomas is reported. Seventy-three (73) core biopsies containing pure flat epithelial atypia were identified from our files, meeting inclusion criteria for the study. In the subsequent excision biopsies, five (7%) cases contained invasive carcinoma or ductal carcinoma in situ and seventeen (23%) contained atypical ductal hyperplasia or lobular neoplasia. All of the ductal carcinoma in situ cases with estrogen receptor results were estrogen receptor positive and intermediate grade. The invasive tumors were small (pT1a) hormone receptorpositive, HER2-negative, low-grade invasive ductal or tubular carcinomas with negative sentinel lymph-node biopsies. No upgrades were identified in the 14 patients who had all of their calcifications removed by the stereotactic core biopsy. Our rate of upgrade to carcinoma, once cases with discordant imaging are excluded, is at the lower end of the range reported in the literature. Given the low upgrade rate and indolent nature of the carcinomas associated with flat epithelial atypia, case management may be individualized based on clinical and radiographic findings. Excision may not be necessary for patients without remaining calcifications following core biopsy.

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Morphologic and Molecular Evolutionary Pathways of Low Nuclear Grade Invasive Breast Cancers and Their Putative Precursor Lesions: Further Evidence to Support the Concept of Low Nuclear Grade Breast Neoplasia Family

Cited by 218 publications

References 39 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

Clinicopathologic characteristics of carcinomas that develop after a biopsy containing columnar cell lesions

Management of flat epithelial atypia on breast core biopsy may be individualized based on correlation with imaging studies

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