Surgical implications and variability in the use of the flat epithelial atypia diagnosis on breast biopsy specimens

Abstract

Objectives: Flat epithelial atypia (FEA) is a relatively new diagnostic term with uncertain clinical significance for surgical management. Any implied risk of invasive breast cancer associated with FEA is contingent upon diagnostic reproducibility, yet little is known regarding its use.

Materials and methods: Pathologists in the Breast Pathology Study interpreted one of four 60-case test sets, one slide per case, constructed from 240 breast biopsy specimens. An electronic data form with standardized diagnostic categories was used; participants were instructed to indicate all diagnoses present. We assessed participants' use of FEA as a diagnostic term within: 1) each test set; 2) 72 cases classified by reference as benign without FEA; and 3) six cases classified by reference as FEA. 115 pathologists participated, providing 6900 total independent assessments.

Results: Notation of FEA ranged from 0% to 35% of the cases interpreted, with most pathologists noting FEA on 4 or more test cases. At least one participant noted FEA in 34 of the 72 benign non-FEA cases. For the 6 reference FEA cases, participant agreement with the case reference FEA diagnosis ranged from 17% to 52%; diagnoses noted by participating pathologists for these FEA cases included columnar cell hyperplasia, usual ductal hyperplasia, atypical lobular hyperplasia, and atypical ductal hyperplasia.

Conclusions: We observed wide variation in the diagnosis of FEA among U.S. pathologists. This suggests that perceptions of diagnostic criteria and any implied risk associated with FEA may also vary. Surgical excision following a core biopsy diagnosis of FEA should be reconsidered and studied further.

Keywords: Atypia; Biopsy; Breast oncology; Flat epithelial atypia; Observer variability.

Fig. 1

Percentage of B-Path test set cases interpreted as having FEA present on the glass slide, with results shown for each participating pathologist and the three reference pathologists, organized according to test set^a a. Each test set was composed of 60 cases. Cases may have been given other higher order interpretations along with the diagnosis of FEA. Cases with higher order interpretations and cases identified as FEA by only a single reference panel pathologist were not used as reference FEA cases.

Fig. 2

Frequency of diagnostic terms used by participating pathologists for reference FEA cases^a a. All six reference FEA cases had FEA only, or a combination of FEA and other lesions categorized as benign without atypia according to the reference panel. Percentages add up to >100% because participants could mark combinations of lesion types for a single case. See Appendix B for a table showing the reference diagnosis for each case and the number of participants who interpreted each lesion.

Fig. 3. Images and discussion points for three cases classified as FEA by reference pathologists

Fig. 3a) Case #1 Focus of FEA with intraluminal secretions. This lesion has round to ovoid monomorphic nuclei with some cellular stratification. In areas, the cells are oriented perpendicularly to the basement membrane reminiscent of columnar cell change, but in other areas, the cells lose this arrangement. Note the lack of slender, bland nuclei typical of columnar cell change and the presence of the more rounded nuclear contour of FEA. 2 of the 3 reference pathologists diagnosed this case as FEA. 52% of participating pathologists (N=29) interpreted this as FEA. Hematoxylin and eosin, 400X and 40X Fig. 3b) Case #3 Focus of FEA in an enlarged TDLU. From low magnification (inset), note the dilated, hyperchromatic ducts that raise concern for FEA at scanning magnification. At higher magnification, the ducts are filled with rounded monomorphic cells that are not regularly oriented perpendicular to the basement membrane. There is cellular stratification and, although there are no prominent nucleoli or obvious chromatin margination, the cells resemble those seen in low grade ductal carcinoma in-situ. This lesion was interpreted as FEA by 34% of participating pathologists (N=29) Fig. 3c) Case #5 Focus of FEA with prominent apical cytoplasmic snouting. From scanning magnification (inset), there are dilated ducts with round contours and hyperchromasia suggestive of FEA. At higher magnification, although there is no cellular stratification, the nuclei are round with a high nuclear to cytoplasmic ratio and prominent chromatin margination characteristic of FEA. 2 of the 3 reference pathologists diagnosed this case as FEA. This lesion was interpreted as FEA by 24% of participating pathologists (N=29)

Fig. 4. Images and discussion points for three cases classified as benign or ALH without FEA by reference pathologists. These cases were frequently interpreted as FEA by participating pathologists

Fig. 4a) Case #7 Focus of columnar cell change and columnar cell hyperplasia in enlarged TLDUs with intraluminal calcifications. Although the nuclei of the cells lining the TLDUs in this lesion show mild pleomorphism, the cells are arranged perpendicularly to the basement membrane and do not have the round to ovoid monomorphic nuclei typical of FEA. The nuclear pleomorphism likely results from reaction to the intraluminal calcification. This lesion was interpreted as FEA by 67% of participating pathologists (N=27). Hematoxylin and eosin, 400X and 40X Fig. 4b) Case #8 Focus of non-atypical proliferative change with enlarged terminal ductal lobular units (TLDUs) with irregular contours and usual ductal hyperplasia. Although from low power (see inset), the lesion is hyperchromatic, raising the possibility of FEA, at higher power, the cells are cytologically benign and are arranged in a haphazard pattern with poorly defined borders characteristic of usual ductal hyperplasia. Note the absence of low grade monomorphic round to ovoid nuclei typical of FEA. This lesion was interpreted as FEA by 37% of participating pathologists (N=30) Fig. 4c) Case #10 Focus of columnar cell change in enlarged TDLUs. From low magnification (inset) the lesion has dilated ducts with round contours and mild hyperchromasia that is suggestive of FEA. However, at higher magnification, there is a single layer of non-atypical columnar to cuboidal cells with cytoplasmic snouts, intraluminal secretions and calcifications. The nuclei are arranged perpendicular to the basement membrane with evenly dispersed chromatin and no obvious nucleoli. These are features more consistent with columnar cell change rather than FEA. This lesion was interpreted as FEA by 23% of participating pathologists (N=30)