Inter-observer agreement in the diagnosis of breast atypical ductal hyperplasia: A systematic review

1. Introduction

Atypical ductal hyperplasia (ADH) is the most common high-risk proliferative lesion in breast cancer [1]. It is defined as a proliferative epithelial lesion that has cytological and architectural characteristics similar to those of low-grade ductal carcinoma in situ (DCIS) but with less compromise in the architecture, degree of involvement of the terminal lobular duct unit, and extension [2]. Page et al. [3] proposed a cut-off of <2 involved spaces to classify a lesion as ADH, but Tavassoli and Norris proposed that lesions ≤2 mm in contiguous extent be classified as ADH considering that using the involvement of at least two spaces was prone to confusion [4].

It is considered a non-obligatory precursor and independent risk factor for developing invasive breast cancer [5–7]. Its diagnosis is associated with a 3 to 5 fold-increased risk of developing invasive breast carcinoma in either breast, although some studies have found a higher risk in the ipsilateral breast [2]. The cumulative incidence of breast cancer with a previous diagnosis of hyperplasia atypical ductal is estimated between 17 and 26% at 10 years and almost 30% at 25 years [8–10].

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Fig. 1.

Information flow through the different phases of the systematic review.

Percutaneous core needle biopsy is a widely used procedure for diagnosing breast disease [11–14] due to its diagnostic performance, low rate of complications, minimal incision, acceptance [14], and ease of the technique in an outpatient setting. However, in atypical ductal hyperplasia, because a major difference from low-grade ductal carcinoma in situ is the extent of the lesion, the distinction between these two histologies is not always easy on breast core needle biopsies because the size of the biopsy creates the possibility of undersampling the lesion. To remedy this limitation, if what is identified in the biopsy is atypical ductal hyperplasia, it is recommended to perform an open biopsy [7] which is considered the standard management [15] and with which 10 to 20% of cases are reclassified in recent studies as ductal carcinoma in situ or invasive cases [2]. Even with open biopsy, it is unlikely that a perfect agreement will be achieved, even strictly complying with the current criteria, considering these are arbitrary and more quantitative than qualitative [2].

The pathological diagnosis of breast biopsy is often considered the gold standard for patient management, but it has significant diagnostic variation, being more susceptible to errors than in other areas of surgical pathology [16]. This variation frequently occurs among pathologists in the diagnosis of atypia so that many benign without atypia breast biopsies might be interpreted as having atypia [17], but also in the analysis of other parameters, so the diagnosis can result in a subjective assessment, prone to variability between observers and limited by the amount of tissue obtained [18]. In breast pathology, a particularly problematic area is the distinction between atypical ductal hyperplasia ADH and low-grade ductal carcinoma in situ of limited extention [2]; These are lesions that exist in a biological continuum but have been separated artifactually based on subtle histologic and extensional differences.

Learning the reproducibility of the diagnosis of atypical ductal hyperplasia becomes important to surgeons who rely on the pathologist’s interpretation to guide their management recommendations. This study reviews the studies that have assessed the consistency of the histological diagnosis of atypical ductal hyperplasia of the breast using the kappa statistic [19].

A systematic review of articles registered in the PubMed database with the terms “pathologists” and “Atypical ductal hyperplasia”, “Atypical ductal hyperplasia” and “interobserver variability”, in Embase with “interobserver agreement in Atypical ductal hyperplasia” and Lilacs with the Spanish terms “patólogos” and “hiperplasia ductal atípica”, without the use of filters, between 03/16/2022 and 03/26/2022 searching for articles with the evaluation of inter-observer agreement in the diagnosis of atypical ductal hyperplasia by using the kappa statistic. Review articles, conference proceedings, and commentaries were excluded.

Search terms were provided by the author; with another reviewer, the articles on the objective of the research were selected, according to the title, or by additional information in the abstract. Discrepancies were resolved by reviewing the full article and by a mutual agreement. In the articles that continued to be evaluated, the author reviewed the entire article to ensure the relevance of the articles with the objective of the research.

3. Results

With the search terms, 507 publications were found. Of these, 491 were excluded in the screening by title and abstract, 55 of them because they were repeated articles in the search. The rest were excluded because they did not correspond to the objective of the research, were part of the exclusion criteria and in one the reason was the language (Chinese). From the remaining review of 16 full articles, 10 were excluded mostly because they did not assess inter-observer agreement in the diagnosis of atypical ductal hyperplasia by using the kappa statistic, and 6 were finally selected for qualitative analysis (Fig. 1). These are summarized in Table 1. The kappa values were scored according to Table 2. The strength of agreement in the extracted studies ranged from slight agreement, kappa = 0.17, to substantial agreement, 0.69, obtained by pathologists dedicated or experienced in breast pathology and who received a prior tutorial.