Discrepancies in the diagnosis of intraductal proliferative lesions of the breast and its management implications: results of a multinational survey

These results indicate that 15 and 20 years postintroduction of criteria for separation of ADH from DCIS [21, 31], interobserver variability in the diagnosis of intraductal proliferative lesions of the breast has not diminished. Given the significance of margin involvement or proximity in current management of DCIS, this survey demonstrates an even wider variability that exists in the management of such lesions and ultimately patient care.

In a survey done by Rosai in 1991, 17 ductal and lobular proliferative breast lesions were distributed among five experts in breast pathology [24]. The participants were asked to categorize such lesions, which had already been circled on glass slides, as either hyperplasia, atypical hyperplasia, carcinoma in situ, or “other” (to be specified) based on the diagnostic criteria they used in their daily practice. In that study, there was no a single case in which all five pathologists agreed on the diagnosis, and there were only three cases (18%) in which four of the five pathologists agreed. Also, some pathologists tended to make more malignant diagnoses than others. In his report, Rosai considered this interobserver variability to be unacceptably high and suggested the adoption of a terminology such as mammary intraepithelial neoplasia with a grading system similar to that which was being used for the uterine cervix.

A possible explanation for such a high degree of interobserver variability set forth in that report was that the pathologists were not using a standard set of criteria. Therefore, a year later, Schnitt et al. [27] tried a different approach to assess interobserver variability in the diagnosis of intraductal proliferative lesions of the breast. In their 1992 survey, they asked six experts in breast pathology to evaluate 24 proliferative ductal lesions. In this survey, the participating pathologists agreed to use the criteria of Page et al., and 15 teaching slides representing classic examples of usual ductal hyperplasia, atypical ductal hyperplasia, and noncomedo DCIS were circulated among the six pathologists to foster concordance before initiation of the study. The specific area of interest on each study slide was indicated by masking all the surrounding tissue so that all the participants focused on the same lesion and to prevent any bias that may result from assessment of changes in the surrounding breast tissue. The participants in this survey were asked to adhere to the provided criteria rather than the ones they used in their daily practice. Despite all these efforts, there was complete agreement among all six pathologists in only 14 (58%) of the 24 cases and among five or more pathologists in 17 cases (71%). The most common diagnostic problem was the distinction of atypical hyperplasia from DCIS in six cases. Although this study showed a significant improvement in interobserver agreement compared to Rosai’s survey, the persistence of significant differences among expert breast pathologists even under optimal and highly artificial conditions conveyed a more widespread problem in the pathology community with potential impact on patient management.

Responses to the current survey also demonstrate that although criteria to distinguish ADH from DCIS have been introduced over two decades ago, there is still no agreement on how to categorize these two types of mammary intraductal proliferation. While the sole partially involved duct described in question 1 would not qualify as DCIS according to the criteria set forth by either Page et al. or Tavassoli and Norris, 43.5% of practicing pathologists, nevertheless, diagnosed it as DCIS. This might seem logical because the partially involved duct probably reflects an extension of the same process present in the nearby unequivocal cribriform DCIS. However, the fact remains that there is no consensus on what to designate a partially involved duct adjacent to unequivocal LG-DCIS and how to manage such a lesion when it is near or on the surgical excision margin [10]. Even among the respondents who considered the partially involved duct in question 1 as ADH, more than a third recommended reexcision if it were close to the margin of resection, and of those who considered this partially involved duct as DCIS, close to 30% would not recommend reexcision even if the in situ carcinoma were within 0.1 mm of the resection margin. This interobserver variability in diagnosis and management was so high that, in the end, patients would have an almost 50:50 chance of having a reexcision or not, regardless of the diagnosis of the partially involved duct as ADH or DCIS. This was due to a combination of the high proportion diagnosing it as DCIS and the high proportion of those who recommended reexcision even though they interpreted it as ADH. Obviously, the impact of this issue goes beyond simply margin involvement; it is also crucial in the assessment of lesion size, resulting in widely varied assessment of size/extent of LG-DCIS.

Question 2 addressed the concept of extensive ADH. Cognizant of the fact that available criteria require complete involvement of duct cross sections for a diagnosis of low-grade (cribriform or micropapillary) variants of DCIS, it was surprising to find that even when only five ducts were involved by a partial cribriform proliferation, over 35% of the respondents considered it as DCIS. Furthermore, when greater than 20 ducts were partially involved by such a cribriform proliferation, the proportion of respondents who treated it as DCIS rose significantly to over 60%. Chi-square testing showed that as the number of partially involved ducts increased, the number of patients diagnosed with cancer significantly increased. Nevertheless, even with drastic differences in the number of involved ducts (5 vs ≥20), there was no unanimity in the diagnosis of carcinoma in situ vs atypical hyperplasia.

This scenario has become increasingly more frequent since the introduction of screening mammography. It was not addressed in the criteria introduced by either Page et al. or Tavassoli and Norris because both those retrospective studies were based on predominantly premammographic era biopsies. With the increasing number of such “extensive ADH” cases (≥ 20 partially involved ducts) seen in her consultation practice, Tavassoli suggested that even when these are designated as extensive ADH due to strict adherence to previously defined criteria, they should be managed as DCIS and reexcised if close to or at the margin of resection [29].

Question 3 demonstrated that the majority of respondents used the 2-mm size criterion rather than the two spaces in diagnosing DCIS. When the single duct described in the question measured greater than 2 mm (4 mm), close to 95% of the respondents considered it DCIS. However, if this single duct measured less than 2 mm, i.e., 0.5 or 1.5 mm, 22.6 and 31.3% of the respondents considered it DCIS, respectively. Although this difference in the probability of diagnosing DCIS when the lesion measured less than or greater than 2 mm was statistically significant, it is interesting to note that over 30% of the respondents considered a single duct measuring 1.5 mm as DCIS and over 20% designated a single duct measuring only 0.5 mm as carcinoma in situ despite the fact that these two scenarios meet neither the criteria of Page et al., which require two completely involved spaces not otherwise specified as to size [21], nor the criteria of Tavassoli and Norris, which require one or more spaces greater than 2 mm in maximal cross-sectional diameter [31]. Even with a substantial 4 mm duct, 5.2% did not designate the lesion as DCIS presumably because of the two-space requirement of Page et al. These responses demonstrate that in the current day to day practice of pathology, some women with a 0.5-mm lesion would be diagnosed as having DCIS, with a reexcision if it were close to or at the resection margin, and most probably radiation therapy, whereas some women with 4 mm lesions interpreted as ADH would get no reexcision, would be simply followed up, or at most would enter some form of prevention trial with hormone therapy [2, 9].

Question 4 in our survey documented the confusion that exists regarding the management of flat epithelial atypia, with over 20% of respondents recommending reexcision if the lesion were close to an excision margin. As a result, over a fifth of the patients would have reexcision, while the remaining 80% would not.

The last question showed the various approaches pathologists take in measuring invasive carcinoma when multifocal early invasion emanating from a single duct is present. Although over 80% of respondents would consider foci of invasion less than 1 mm emanating from opposite poles of a duct with DCIS as microinvasion, slightly over 16% of respondents would measure DCIS with its associated microinvasion from opposite poles as one continuous invasive carcinoma, which would entail a drastically different treatment approach.

The results of this survey raise numerous questions about studies performed in different countries and even different institutions within the same country regarding risk factors, treatment, prognosis, and outcome of intraductal proliferative lesions of the breast, which include LG-DCIS and/or ADH—a significant proportion of mammographically detected noninvasive lesions. Even when the criteria used are explicitly stated, application of criteria varies remarkably among pathologists and from one study to the next. Certainly, the issues raised in this study are not uncommon but have not been specifically addressed in any of the major single-, multiinstitutional, or multinational studies on DCIS cases that include LG-DCIS. Most if not all such studies lack a central review of the diagnosis and even many rely on multiple pathologists at sometimes multiple institutions. This study also illustrates that 15 to 20 years of education of pathologists at local, national, and international courses has not helped much in increasing the level of agreement and uniformity in the diagnosis and interpretation of these common lesions using the criteria available for separating ADH from LG-DCIS. Chi-square testing failed to reveal any statistically significant difference in the response behavior of expert breast pathologists and pathologists who did not consider themselves experts.

Since the institution of widespread screening mammography, the number of early, LG-DCIS lesions that are diagnosed has dramatically increased [13, 14, 19]. How partially involved ducts, often spread around completely involved ducts, are interpreted could change the size/extent of the lesion by several centimeters. This potentially undermines the internal consistency and comparability of epidemiological studies and clinical trials regarding such lesions.

In his 1991 survey, Rosai lamented the fact that there were no known morphometric, ultrastructural, immunohistochemical, or molecular features to distinguish ADH from LG-DCIS [24]. Unfortunately, this issue continues to be the case [1, 11, 15, 16, 18, 25]. Pathologists must assign lesions within the ADH–DCIS continuum to one end of the spectrum or the other based on the morphologic features present on an H&E-stained slide and an arbitrary set of quantitative criteria that cannot be applied to every lesion encountered. Not only the subjective nature of interpreting the morphologic findings but also the existence of different and in some cases conflicting diagnostic criteria create considerable interobserver variability in distinguishing ADH from LG-DCIS.

This diagnostic variability in turn leads to confusion regarding the optimal management approach to such intraductal proliferative lesions because a diagnosis of LG-DCIS is automatically associated with a significantly worse prognosis and usually requires a more drastic surgical approach compared to ADH. Furthermore, the negative impact of the diagnosis of “carcinoma”, albeit an in situ one, on patients’ psychological well-being (depression and anxiety) has been well documented [12, 23] and should be a consideration in the choice of optimal terminology.

Molecular, immunohistochemical, and morphologic similarities indicate that the only difference between ADH and LG-DCIS is a quantitative one [1, 11, 15, 16, 18, 25]. The claim that separation of ADH from LG-DCIS is justified based on the development of carcinomas post-ADH in either breast while those that develop after LG-DCIS occur in the same breast is questionable [20, 22, 26]. Over a period of 23 years, three papers have appeared on this topic based on a group of 28 women with a median follow-up of 31 years, noting that the invasive carcinomas that occur after LG-DCIS treated by biopsy alone develop in the same breast and in the same quadrant from which the original biopsy with DCIS was taken. Seven of the 11 women who developed subsequent invasive carcinoma were diagnosed within 10 years of the DCIS biopsy, 1 was diagnosed within 12 years, and the remaining 3 developed infiltrating carcinomas over 23–42 years. The authors conclude that these results “indicate a striking dividing point biologically and histopathologically between LG-DCIS lesions and the cytologically similar but lesser lesions of ADH” [26]. When 7 of the 28 women developed invasive carcinoma within 10 years, one wonders why the remaining patients were not contacted to receive appropriate therapy for their disease rather than continuing the study for another 20 years.

Judging from the microscopic description and the sampling documented for these 28 cases, a substantial number of these lesions were probably not low grade because they had some atypia and/or necrosis, albeit not diffusely, suggesting that those who died within 10 years most likely had substantial amount of residual disease and/or higher grade DCIS lesions [6]. The gross and pathologic features of these 28 cases are described in detail in the initial paper published in 1982, which did not refer to them as low grade [20]. Therefore, it is more likely that this study reflects the natural history of a wide variety of intraductal carcinomas, only some of which were LG-DCIS. A more simple explanation for any differences that might exist between ADH and LG-DCIS in the frequency of subsequent progression would be that a minuscule lesion, once totally removed, results in near equalization of the risk for subsequent development of carcinoma in the two breasts of that individual patient. A more extensive process, however, is less likely to be completely eliminated by conservative surgical excision alone, leading to the development of recurrences at the same site due to residual disease [6].

A recent epidemiological study has shown a nearly equal incidence rate (5.4 vs 4.5/1,000 person-years) for development of subsequent invasive carcinoma in either breast after a diagnosis of DCIS among close to 37,700 patients diagnosed between January 1988 and December 2002, many of whom were treated by surgery and radiation therapy [17]. This confirms the fact that once a DCIS is adequately treated, it results in equalization of risk for either breast. Furthermore, it indicates that complete excision is an adequate therapy for small lesions. Therefore, complete excision with adequate margins should be explored further as the only therapy for small DIN 1 (DCIS grade 1) lesions that do not exceed 3–4 mm in maximum extent, particularly when there is no evidence of even any flat epithelial atypia around the DCIS.

It seems only logical to adopt a terminology in which two morphologically identical lesions are not given diagnostic designations as different as “hyperplasia” and “carcinoma”. The use of the DIN terminology may help solve this problem [28, 30]. Although the DIN terminology does not claim to reduce interobserver variability, it diminishes the effect of drastically different designations for similar lesions by including the spectrum of atypical ductal hyperplasia and LG-DCIS under the umbrella designation of grade 1 DIN.