Interobserver Reproducibility in the Diagnosis of Ductal Proliferative Breast Lesions Using Standardized Criteria

Schnitt, Stuart J.; Connolly, James L.; Tavassoli, Fattaneh A.; Fechner, Robert E.; Kempson, Richard L.; Gelman, Rebecca; Page, David L.

doi:10.1097/00000478-199212000-00001

Cited by 380 publications

(193 citation statements)

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“…In fact, the level of agreement we observed among eight pathologists in this study was higher than that seen in prior studies of observer agreement in proliferative breast lesions, even those in which standardized criteria were employed. 32 There are a number of potential limitations to this study. First, it could be argued that our results may not be representative of the level of agreement attainable in general pathology practice because all of the pathologists participating in this study have a particular interest in breast pathology.…”

Section: Discussionmentioning

confidence: 96%

“…[28][29][30][31][32][33] One conclusion that can be drawn from these studies is that observer agreement is fostered by the use of standardized histologic criteria by the study participants. In keeping with this observation, the results of this study demonstrate for the first time that FEA, as defined by the WHO Working Group, can be distinguished from non-atypical CCLs with a high degree of consistency using available diagnostic criteria.…”

Section: Discussionmentioning

confidence: 99%

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Interobserver reproducibility in the diagnosis of flat epithelial atypia of the breast

et al. 2006

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and 8 Addenbrooke's NHS Trust, Cambridge, UK Columnar cell lesions (CCLs) of the breast with low-grade/monomorphic-type cytologic atypia are being identified increasingly in biopsies performed owing to mammographic microcalcifications. The WHO Working Group on the Pathology and Genetics of Tumours of the Breast recently introduced the term 'flat epithelial atypia' (FEA) for these lesions. However, the ability of pathologists to reproducibly diagnose FEA and to distinguish it from CCLs without atypia has not been previously evaluated. Eight pathologists with an interest in breast pathology participated in a study to address this issue. The study reference pathologist provided the other seven study pathologists with a Powerpoint tutorial that included written criteria for, and representative images of, FEA and CCLs without atypia (ie, columnar cell change and columnar cell hyperplasia). Following review of the tutorial, the study pathologists examined images in Powerpoint format from 30 CCLs and were instructed to categorize each as either 'FEA' or 'not atypical'. Overall agreement among the eight pathologists was 91.8% (95% CI, 84.0-96.9%), and the multi-rater kappa value was 0.83 (95% CI, 0.67-0.94), which is within the 'excellent agreement' range. Agreement was slightly better for determining absence of FEA (92.8%: 95% CI, 84.1-97.4%), than for determining its presence (90.4%: 95% CI, 79.9-96.7%). We conclude that the diagnosis of FEA and its distinction from CCLs without atypia is highly reproducible with the use of available diagnostic criteria.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Interobserver reproducibility in the diagnosis of flat epithelial atypia of the breast

et al. 2006

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“…Usual and atypical ductal hyperplasias were classified using the criteria of Page, Schnitt and others, 24,25 and the columnar cell lesion spectrum classified using the criteria of Schnitt et al 24,26 Slides were reviewed to confirm histologic diagnosis and select lesions for genotyping. Where available, a spectrum of lesions was isolated from the same specimen, including proliferative lesions, atypical lesions, in situ, invasive, and/or metastatic carcinoma.…”

Section: Methodsmentioning

confidence: 99%

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

et al. 2014

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The phosphatidylinositol-3-kinase pathway is one of the most commonly altered molecular pathways in invasive breast carcinoma, with phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) mutations in 25% of invasive carcinomas. Ductal carcinoma in situ (DCIS), benign papillomas, and small numbers of columnar cell lesions harbor an analogous spectrum of PIK3CA and AKT1 mutations, yet there is little data on usual ductal hyperplasia and atypical ductal and lobular neoplasias. We screened 192 formalin-fixed paraffin-embedded breast lesions from 75 patients for point mutations using a multiplexed panel encompassing 643 point mutations across 53 genes, including 58 PIK3CA substitutions. PIK3CA point mutations were identified in 31/62 (50%) proliferative lesions (usual ductal hyperplasia and columnar cell change), 10/14 (71%) atypical hyperplasias (atypical ductal hyperplasia and flat epithelial atypia), 7/16 (44%) lobular neoplasias (atypical lobular hyperplasia and lobular carcinoma in situ), 10/21 (48%) DCIS, and 13/37 (35%) invasive carcinomas. In genotyping multiple lesions of different stage from the same patient/specimen, we found considerable heterogeneity; most notably, in 12 specimens the proliferative lesion was PIK3CA mutant but the concurrent carcinoma was wild type. In 11 additional specimens, proliferative epithelium and cancer contained different point mutations. The frequently discordant genotypes of usual ductal hyperplasia/columnar cell change and concurrent carcinoma support a role for PIK3CA-activating point mutations in breast epithelial proliferation, perhaps more so than transformation. Further, these data suggest that proliferative breast lesions are heterogeneous and may represent non-obligate precursors of invasive carcinoma. Keywords: atypical ductal hyperplasia; breast carcinoma; columnar cell change; PIK3CA; usual ductal hyperplasia The phosphatidylinositol-3-kinase pathway is one of the most commonly mutated pathways in invasive breast carcinoma. Activating mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are present in B25% of invasive carcinomas and are present in an even higher percentage (on the order of 40%) of low-grade estrogen receptorpositive carcinomas (luminal A intrinsic subtype). 1-10 PIK3CA mutations cluster in 'hotspots' in exon 9 (helical domain, E542K and E545K) and exon 20 (kinase domain, H1047R/L). [1][2][3][4][5][6][7][8][9][10] In addition, this pathway is activated by mutations in the plekstrinhomology domain of AKT1 in B5% of breast carcinomas, by the loss of the phosphatase PTEN (phosphatase and tensin homolog on chromosome 10), or rarely by amplification or alterations in other regulatory subunits, and is a target of active drug development. [8][9][10][11] In recent large studies of estrogen receptor-positive tumors, the presence of activating PIK3CA hotspot point mutations has been paradoxically associated with more favorable outcome as compared with breast carcinomas with wild-type PIK3CA. 3,12,13 We and other groups have previously s...

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“…The diagnostic criteria for EHLA are those previously given for moderate or florid hyperplasia. 5,[13][14][15][16] We performed immunostaining using an affinity-purified mouse monoclonal antibody against ER␣ (6F-11; Zymed Laboratories, South San Francisco, CA) and the streptoavidin-biotin immunoperoxidase method. Immunohistochemical stains were evaluated in individual EHLA lesions and in at least 3 adjacent histologically normal ducts and lobular units without knowledge of subsequent cancer outcome.…”

Section: Methodsmentioning

confidence: 99%

Breast cancer risk associated with estrogen receptor expression in epithelial hyperplasia lacking atypia and adjacent lobular units

Gobbi

Dupont

Parl

et al. 2004

Intl Journal of Cancer

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Estrogen is associated with many epidemiologic risk factors for invasive breast cancer. Cells that express estrogen receptors (ERs) in epithelial hyperplasia lacking atypia (EHLA) may influence breast cancer progression. We conducted a nested case-control study of 268 women with biopsy-confirmed EHLA to determine whether immunohistochemical expression of ER␣ in EHLA affects subsequent breast cancer risk. Study subjects could not have a prior or current history of breast cancer or atypical hyperplasia. Knowledge of molecular markers of breast neoplastic progression may help identify women at high risk for breast cancer. Such markers would facilitate the development of prophylactic therapies for premalignant breast disease. 1 Estrogen has long been associated with stimulating the normal growth of breast epithelial cells and may also be associated with many epidemiologic risk factors for invasive breast cancer. Estrogen acts on cells via the estrogen receptors (ERs) to stimulate their mitogenic activity. 2 Comparison of normal and precancerous breast biopsies has shown that ER expression is relatively low in normal epithelium and higher in atypical ductal hyperplasia and carcinomas in situ. 3,4 The earliest lesion associated with breast cancer is epithelial hyperplasia lacking atypia (EHLA), which has a 1.5-to 2-fold increased risk of development of breast cancer. 5-8 A slight increase in ER-positive cells has been described in these earliest lesions. 3 In our study, we investigated the relationship between ER␣ expression in EHLA and subsequent risk of invasive breast cancer. Material and methodsWe conducted a retrospective nested case-control study of women from the Nashville Breast Cohort Study. 5,9 -11 This cohort consists of women who underwent benign breast biopsy at 1 of 3 hospitals in Nashville, Tennessee. Successful follow-up in this cohort has been achieved for 90% of study subjects. Women with prior or concurrent invasive breast cancer were excluded from this cohort. Cohort members were eligible for inclusion in this study if their entry biopsy contained EHLA and were performed between 1965 and 1982. This study subcohort consisted of 1,680 women. The average length of follow-up for these patients was 15.4 years. Cases consisted of all eligible subjects who subsequently developed invasive breast cancer. Two controls were selected for each case matched by age at biopsy and year of biopsy. To be selected as a control for a specific case, a patient had to be in the risk set for that case at the time when the case patient developed breast cancer, 12 that is, her breast cancer-free follow-up had to be at least as long as that of the case under consideration. Selected controls could subsequently become cases, which in fact happened for 8 women. Each of these subjects was included as a control in one set of matched case-control triplets and as a case in another. There were 92 cases who developed breast cancer on follow-up who were matched to 184 controls. Since 8 of these controls subsequently became cases, this...

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Interobserver Reproducibility in the Diagnosis of Ductal Proliferative Breast Lesions Using Standardized Criteria

Cited by 380 publications

References 0 publications

Interobserver reproducibility in the diagnosis of flat epithelial atypia of the breast

Interobserver reproducibility in the diagnosis of flat epithelial atypia of the breast

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

Breast cancer risk associated with estrogen receptor expression in epithelial hyperplasia lacking atypia and adjacent lobular units

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