Histological features associated with diagnostic agreement in atypical ductal hyperplasia of the breast: illustrative cases from the B-Path study

Abstract

Aims: This study examined the case-specific characteristics associated with interobserver diagnostic agreement in atypical ductal hyperplasia (ADH) of the breast.

Methods and results: Seventy-two test set cases with a consensus diagnosis of ADH from the B-Path study were evaluated. Cases were scored for 17 histological features, which were then correlated with the participant agreement with the consensus ADH diagnosis. Participating pathologists' perceptions of case difficulty, borderline features or whether they would obtain a second opinion were also examined for associations with agreement. Of the 2070 participant interpretations of the 72 consensus ADH cases, 48% were scored by participants as difficult and 45% as borderline between two diagnoses; the presence of both of these features was significantly associated with increased agreement (P < 0.001). A second opinion would have been obtained in 80% of interpretations, and this was associated with increased agreement (P < 0.001). Diagnostic agreement ranged from 10% to 89% on a case-by-case basis. Cases with papillary lesions, cribriform architecture and obvious cytological monotony were associated with higher agreement. Lower agreement rates were associated with solid or micropapillary architecture, borderline cytological monotony, or cases without a diagnostic area that was obvious on low power.

Conclusions: The results of this study suggest that pathologists frequently recognize the challenge of ADH cases, with some cases being more prone to diagnostic variability. In addition, there are specific histological features associated with diagnostic agreement on ADH cases. Multiple example images from cases in this test set are provided to serve as educational illustrations of these challenges.

Keywords: B-Path study; atypical ductal hyperplasia; breast pathology; diagnostic agreement; interobserver agreement.

Figure 1

Scoring Form for Histologic Features Evaluated in 72 Expert Consensus ADH Cases

Figure 2

Spectrum of Diagnoses Recorded by Participating Pathologists in the 72 Cases with an Expert Consensus Diagnosis of ADH

Figure 3

Photos of the diagnostic areas from the two cases with the highest participant agreement with the consensus diagnosis of ADH. Both cases had focal lesions, less than 2 mm (and < 2 membrane bound spaces), that were obvious on low power, had obvious cytologic monotony and a cribriform architectural pattern. A–B) A case with 83% of participant agreement with the expert consensus diagnosis of ADH; 7% recorded a Benign diagnosis (UDH), and 10% recorded a DCIS diagnosis for the case (30 total interpretations). C–D) 89% agreed with the consensus diagnosis of ADH; 4% recorded a Benign diagnosis (UDH) and 7% recorded a DCIS diagnosis on the case (27 total interpretations). Lesions with these features should be reproducibly classified as ADH as serve as good examples of this diagnosis.

Figure 4

Papillary lesions with ADH were associated with higher diagnostic agreement than ADH not in a papillary lesion. A–B) 67% of participants recorded a diagnosis of ADH for this papillary lesion; 28% recorded a DCIS diagnosis and 3% a Benign diagnosis (mostly papilloma without atypia) (29 interpretations). C–D) 59% of participants recorded a diagnosis of ADH for this papillary lesion; 31% recorded a Benign diagnosis (mostly papilloma without atypia), and 10% recorded a DCIS diagnosis for the case (29 total interpretations). The first case (A–B) had less discrete areas of atypia in more than one area of the papilloma, making it borderline with DCIS. However, each focus was considered < 2mm and the consensus diagnosis was ADH on this core needle biopsy sample. The second case has a single, more discrete area of cribriform architecture with cytologic monotony within the papillary proliferation measuring < 2 mm. These areas appear distinct from the background normal papillary epithelium or UDH but due to their limited in extent (< 2 mm), they fall short of most pathologists’ threshold for DCIS.

Figure 5

Example of a case with obvious cytologic monotony and cribriform architecture that was close to the 2 mm threshold distinguishing between a diagnosis of ADH versus limited extent low grade DCIS. 60% of participants recorded a diagnosis of ADH, 20% recorded a DCIS, 17% recorded a Benign diagnosis, and 3% an FEA diagnosis for the case (30 total interpretations). When a lesion with these features is close to the extent threshold, diagnostic disagreement is predictable. The lesion involves more than two membrane bound spaces but is close to 2 mm in extent. The expert consensus panel (and majority of participants) applied a more conservative approach with this borderline lesion, classifying it as ADH rather than low grade DCIS. A comment can be included in the report that the lesion is borderline with low grade DCIS.

Figure 6

Example images of the diagnostic area from a case with solid architecture and subtle cytologic monotony. Only 17% of participating pathologists recorded a diagnosis of ADH, with 55% recording the case as LN and 28% as DCIS (29 total interpretations). While the differential diagnosis includes a lobular in situ lesion (ALH/LCIS) that may be resolved with an E-cadherin stain, subtle micro-acini supporting a ductal process are evident on the H&E at high power (panel B).

Figure 7

Examples images from two cases with micropapillary architecture, which was associated with worse diagnostic agreement with the expert consensus diagnosis of ADH. A) Only 28% of participants recorded a diagnosis of ADH on this case, 45% recorded a LN (there was LN also present in multiple foci elsewhere on the slide), 28% recorded a DCIS diagnosis and 0% recorded a Benign diagnosis (29 interpretations). B) Only 24% of participants recorded this case as ADH, with 31% as Benign (mostly columnar cell hyperplasia and UDH), 21% recording the case as FEA and 24% as DCIS (29 total interpretations). Both lesions have scattered micropapillary, club-shaped structures that are only partially involving dilated spaces involved by FEA. Micropapillary patterns can be subtle and easily missed if focal. In the first case (A), the concurrent diagnosis of lobular neoplasia in multiple areas of the same slide may have been a distractor.

Figure 8

Example images from a case with a single region of potential interest to screen but borderline cytologic monotony (ADH vs UDH) and architectural changes that appear cribriform but lack polarized spaces. 31% of participants recorded an ADH diagnosis for the case, 59% recorded a Benign diagnosis (94% UDH) and 7% recorded a LN diagnosis, and 3% recorded a DCIS diagnosis (29 total interpretations). When the both the architectural and the cytologic features are borderline between UDH and ADH, diagnostic disagreement is more likely. Additional levels, immunohistochemistry (CK5/6, ER or the ADH5 stain) and additional opinions can be helpful in this differential if these findings are present on a core needle biopsy where it would be most clinically relevant. Given the findings on the single H&E slide available in this test set, the expert panel classified this lesion as ADH based on the architectural atypia present and subtle monotony. However, the findings are borderline with UDH, which can be mentioned in the report.

Figure 9

Example images from a case with a single region of potential interest to screen but borderline monotony (UDH vs ADH) and solid/subtle architecture. On higher power (panels C and D) subtle microacini are apparent with polarization of cells towards the lumen. This case had an almost even distribution between three diagnostic categories with 31% of participants recording an ADH diagnosis, 34% recording a Benign diagnosis (100% recorded UDH), and 34% recording a DCIS for the case (29 total interpretations). The differential in this case includes UDH due to the nuclear crowding and slit like spaces but also ADH because of the subtle polarized spaces being formed. The subtly hyperchromatic nuclear cytology also raises the differential of a low-intermediate grade DCIS. Additional levels, immunohistochemistry (CK5/6, ER or the ADH5 stain) and additional opinions can be helpful in this differential. Based on the presence of a single lesion measuring < 2 mm and involving only two membrane bound spaces on this H&E alone, classification as ADH was considered the best diagnosis by the expert consensus panel.

Figure 10

Example images from two cases that had a predominantly flat pattern of architecture with only subtle early arches, bridges or micropapillations that the expert consensus panel classified as ADH. A) The cytology is monotonous, with rounded nuclei, and a predominantly flat growth pattern. 33% of participants recorded a highest order diagnosis of FEA in this case, 40% as ADH, 20% as benign, and 7% as DCIS. B) Similarly, the cytology of the second case is monotonous with predominantly a flat growth pattern but very focal, early micropapillae and bridges being formed, consistent with ADH. 23% of participants recorded a highest order diagnosis of FEA in this case, 50% as ADH, 17% as Benign, and 10% as DCIS. When FEA is present, the case should be closely examined for subtle architectural patterns consistent with an ADH diagnosis.