Atypical Ductal Hyperplasia

Interobserver and Intraobserver Variability

Rohit K Jain; Rutika Mehta; Rosen Dimitrov; Lisbeth G Larsson; Paul M Musto; Kurt B Hodges; Thomas M Ulbright; Eyas M Hattab; Narasimhan Agaram; Muhammad T Idrees; Sunil Badve


Mod Pathol. 2011;24(7):917-923. 

In This Article

Abstract and Introduction


Interobserver reproducibility in the diagnosis of benign intraductal proliferative lesions has been poor. The aims of the study were to investigate the inter- and intraobserver variability and the impact of the addition of an immunostain for high- and low-molecular weight keratins on the variability. Nine pathologists reviewed 81 cases of breast proliferative lesions in three stages and assigned each of the lesions to one of the following three diagnoses: usual ductal hyperplasia, atypical ductal hyperplasia and ductal carcinoma in situ. Hematoxylin and eosin slides and corresponding slides stained with ADH-5 cocktail (cytokeratins (CK) 5, 14. 7, 18 and p63) by immunohistochemistry were evaluated. Concordance was evaluated at each stage of the study. The interobserver agreement among the nine pathologists for diagnosing the 81 proliferative breast lesions was fair (κ-value=0.34). The intraobserver κ-value ranged from 0.56 to 0.88 (moderate to strong). Complete agreement among nine pathologists was achieved in only nine (11%) cases, at least eight agreed in 20 (25%) cases and seven or more agreed in 38 (47%) cases. Following immunohistochemical stain, a significant improvement in the interobserver concordance (overall κ-value=0.50) was observed (P=0.015). There was a significant reduction in the total number of atypical ductal hyperplasia diagnosis made by nine pathologists after the use of ADH-5 immunostain. Atypical ductal hyperplasia still remains a diagnostic dilemma with wide variation in both inter- and intraobserver reproducibility among pathologists. The addition of an immunohistochemical stain led to a significant improvement in the concordance rate. More importantly, there was an 8% decrease in the number of lesions classified as atypical ductal hyperplasia in favor of usual hyperplasia; in clinical practice, this could lead to a decrease in the number of surgeries carried out for intraductal proliferative lesions.


Significant progress has been made in the diagnosis and treatment of breast cancer in the last few decades. Screening mammograms have made it possible to detect many tumors at an earlier stage and provide prompt treatment. Mammography has led to detection of increased numbers of breast lesions and subsequent diagnostic biopsies.[1] A spectrum of lesions from benign (usual ductal hyperplasia), borderline (atypical ductal hyperplasia), pre-invasive (ductal carcinoma in situ) to invasive (invasive ductal carcinoma)[2–5] is identified on these biopsies. As usual, ductal hyperplasia carries minimal or no increased risk of breast cancer; these patients do not undergo any additional procedures. On the other hand, atypical ductal hyperplasia and ductal carcinoma in situ progress to invasive carcinoma in nearly 4–5% and 8–10% of cases, respectively.[6] Patients with these lesions are advised excision with the addition of radiation for those with ductal carcinoma in situ. Although the clinical guidelines are well laid out, the histological differentiation between atypical ductal hyperplasia and ductal carcinoma in situ has been difficult. Several previous studies have shown that the concordance among pathologists in diagnosing atypical ductal hyperplasia especially is very poor, giving rise to potential misclassifications in treatment protocols.[7–11] Since atypical ductal hyperplasia and ductal carcinoma in situ comprise 10%[12] and 15–20%,[13] respectively, of mammographically detected breast lesions, it becomes important to provide diagnostic aid to pathologists to recognize these lesions, resulting in better reproducibility.

In this study, we investigated the reproducibility in the interpretation of these intraductal proliferative breast lesions among university-based surgical pathologists. We also explored the observers' consistency in diagnosing these lesions and the impact of the addition of an immunohistochemical marker as a potential tool to differentiate these lesions and improve concordance rate.


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