When only five ducts had a partial cribriform proliferation, 82 In Question 3, as shown in Fig. When a single duct with a complete cribriform pattern measured 0.

Question 4 addressed the approach to management of flat epithelial atypia when it was present in multiple ducts located within less than 0. In this scenario, when multiple ducts with flat epithelial atypia were close to an excision margin, 48 respondents Finally, question 5 evaluated how respondents measured invasive carcinoma when two foci of stromal microinvasion measuring less than 1 mm each emanated from two opposite poles of a 1-cm duct with high-grade comedo-type DCIS Fig.

Chi-square testing was performed to compare the responses of expert breast pathologists and nonexperts to all five questions. No statistically significant difference was found between the two groups in the proportion of responses to any of the questions. 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 , 17 ductal and lobular proliferative breast lesions were distributed among five experts in breast pathology [ 24 ]. 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. In their 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. 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.

The most common diagnostic problem was the distinction of atypical hyperplasia from DCIS in six cases. 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.

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 ].

This interobserver variability in diagnosis and management was so high that, in the end, patients would have an almost 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. Question 2 addressed the concept of extensive ADH.

Chi-square testing showed that as the number of partially involved ducts increased, the number of patients diagnosed with cancer significantly increased. 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. Question 3 demonstrated that the majority of respondents used the 2-mm size criterion rather than the two spaces in diagnosing DCIS. However, if this single duct measured less than 2 mm, i. Even with a substantial 4 mm duct, 5. These responses demonstrate that in the current day to day practice of pathology, some women with a 0. The last question showed the various approaches pathologists take in measuring invasive carcinoma when multifocal early invasion emanating from a single duct is present.

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.

Many authorities believe the patient should undergo complete surgical excision to exclude malignancy and prevent the development of advanced neoplasia if found on a breast biopsy. Surgical excision for core biopsies that show ADH is considered standard of care. However, ALH may be an incidental finding in small biopsies, and standard surgical resection of these lesions is more controversial. In general, excision is usually recommended in high-risk patients.

Short-term follow-up with increased mammography frequency should be recommended for patients in whom surgical resection is not performed. Either can be found in association with or at the periphery of a more advanced lesion; therefore, it is important to remember that atypical hyperplasia found on a biopsy may not accurately represent the greater lesion. Studies have failed to show reliable, independent indicators of which atypical hyperplasia lesions are associated with more aggressive entities such as high-grade DCIS or invasive cancer.

It is important to note that while surgical excision after identifying atypical hyperplasia in a core biopsy is generally considered appropriate, some disagreement persists regarding the management of high-risk lesions in certain cases. Important differential diagnostic entities to consider when viewing possible ADH or ALH include usual ductal hyperplasia, ductal carcinoma in situ, lobular carcinoma in situ, and flat epithelial atypia, with the most important distinguisher being whether a lesion is ADH or low-grade DCIS.

Atypical lobular hyperplasia ALH , like ADH, is another high-risk breast lesion that has been associated with a four-fold to a five-fold increased lifetime risk of developing breast cancer in either the ipsilateral or contralateral breast. Complications of atypical hyperplasia of the breast are related mainly to the surgical treatment of this disease. Infection, bleeding, anesthesia complications, disfigurement, and pain are some, but not all, of the possible complications associated with treatment of this disease.

Atypical hyperplasia of the breast is a complicated disorder, with most experts agreeing that surgical excision is appropriate. Patients should be counseled, however, on an individual basis, as factors that influence the course of treatment may include the extent of disease, atypia, family history, prior history, genetics, and overall patient health status.

Proper management of patients with this complex disease requires collaboration between radiology, surgery, pathology, and the patient and their primary care team. The current standard of care is to excise high-risk breast lesions due to high upgrade rates on the excision of these breast lesions after a biopsy.

Molecular profile of atypical hyperplasia of the breast. Combined histologic and cytologic criteria for the diagnosis of mammary atypical ductal hyperplasia. The breast journal. In ADH there are ducts partially filled with abnormally uniform evenly spaced cells with polarization [ 20 ] Fig. The cells might grow in arcades, rigid bridges, or bars of uniform thickness, micro-papillae, solid or cribriform patterns. The involved spaces might also contain a population of cells with similar characteristics of usual ductal hyperplasia UDH or residual normal epithelium [ 22 ].

One of the major impediments to proper management of ADH is the conflicting definitions of ADH and intra-observer variability which make a definitive diagnosis difficult [ 10 , 23 ]. Ghofrani et al.

Myoepithelial-specific markers such as p63 and myoid markers such as SMA are helpful to demonstrate preservation of myoepithelial cells at the epithelialstroma interface. Collectively, these studies suggest that a more objective biomarker for the differential diagnosis of ADH and LG DCIS would be highly desirable since extent alone cannot differentiate an early neoplastic lesion that may not progress to malignancy from those that represent part of a DCIS process that is underrepresented in the examined specimen and are more likely to progress.

Molecular studies could play an important role to identify such biomarkers; however, given the above described lack of concordance at assessing ADH [ 28 ], any studies related to ADH need to include a strict review procedure by one or more breast pathologists with sufficient experience before inclusion into the study. In terms of the management of the patients, some clinicians prefer to observe patients diagnosed with ADH. However, this option may put those patients at risk of undertreatment.

Given the high upgrade rate, it is not surprising that the majority of clinicians suggest a surgical excision after ADH diagnosis on CNB to rule out concomitant malignancy. For example, if a patient had an area of radiographic abnormality and her CNB showed a focus of atypical cells in keeping with ADH and not sufficient for the diagnosis of LG DCIS, it would be preferable to perform an excision to examine the whole area of abnormality. Because the abnormal radiological mass might be due to a well-developed DCIS, surgical excision could avoid missing a higher risk lesion requiring more intensive treatment [ 31 ].

In this type of upgrade scenario, presumably the most likely explanation for missing a higher risk lesion from a CNB would be sampling limitations. This highlights the important clinical utility of identifying robust biomarkers that can distinguish between pure ADH and ADH that is likely to be associated with a synchronous LG DCIS and thereby avoiding the need for recommending surgical excision for all.

Alternatives to surgical excision include treatment with tamoxifen as this has been reported to reduce the risk of developing breast cancer from 21 to 7. However, recent studies on breast cancer prevention with endocrine therapy show a very low rate of uptake and even lower rate of persistence due to the side effects, even in women at very high genetic risk [ 33 ]. Some parameters may be useful to take into consideration before excision, such as the number of cores, type of needle used, type of lesion, and lesion diameter [ 7 , 10 ].

It has also been suggested to take into account the number of the foci in the core and how much of the radiographic lesion was removed, with multiple foci requiring a greater area to be removed [ 34 ].

None of these parameters or suggestions is clinically proven and prospective validation is required to evaluate such prediction tools. This practice would certainly overtreat the majority of women diagnosed with ADH and clearly demonstrates the need to identify a robust biomarker to avoid unnecessary surgery and optimal management. Unfortunately, risk prediction following ADH diagnosis is controversial [ 7 ], and counseling and further screening for these women diagnosed with ADH are therefore probably not adequate.

Indeed, Degnim et al. One possibility is that this combination indicates a lesion already DCIS at a cellular biology level but lacking the extent to be diagnosed as such. An elevated risk of breast cancer associated with calcification of atypical hyperplasia was, however, reported by Hutchinson et al. The degree of atypia can also vary in ADH, but this is not a feature that has been evaluated in terms of subsequent risk, perhaps because of the difficulty in standardizing such a measure across different pathologists.

The complexities of analyzing focality, calcification, and atypia in terms of how these are measured emphasizes the importance of understanding the breast biology, as well as the precursor versus risk indicator status of ADH. Given the fact that only a fraction of ADH 9. Thus far, despite the high risk of developing cancer associated with ADH, attempts to identify clinicopathological or molecular biomarkers to predict individual risk have been unsuccessful.

Risk reduction strategies remain varied, from active surveillance at one end of the spectrum to prophylactic mastectomy at the other. Breast cancer is well known to be a genetic disease, with very frequent somatic copy number changes, a number of driver mutations such as in PIK3CA and TP53 , and widespread transcriptional deregulation [ 42 ]. While molecular studies of benign breast disease are fewer, they suggest both similarities to and differences from breast carcinoma.

Very few studies have described the molecular genetic features of ADH Table 1 and these are further limited because most were carried out on small numbers of samples using low resolution methodology, such as microsatellite marker-based loss of heterozygosity LOH or allelic imbalance AI analysis and cytogenetic comparative genomic hybridization CGH.

The latter has a genomic resolution of 5—10 Mb, whereas most LOH studies were carried out using only a few markers, which were chosen based on the location of common regions of AI in IDC. One of the major barriers to studying ADH is the limited amount of DNA available, a problem reported by multiple studies [ 43 , 44 ]. This limitation can be overcome by using in situ assays, such as fluorescence in situ hybridization FISH , but at the cost of being highly locus-specific.

Any gains or losses are reported when changes occurred in at least one sample of the cohort. Loss of 16q was also confirmed as a common event in breast cancer by other studies Table 1 , signifying that this event might be particularly important in the early development of breast cancer.

A more sensitive FISH study using nine chromosomal probes supported these observations, finding that all ADH had chromosomal aneuploidy, and the number of cells with aneuploidy was higher than in lesions without atypia, although less frequent than in carcinomas [ 51 ].

Using alternative methods, Gao et al. Firstly, they found that gain at 19p and losses at 2p, 6q, 11p, 12q, 22q, and Xq were only present in DCIS and IDC, suggesting that these changes might be a later event in breast cancer progression.

Secondly, ADH had a high prevalence of 17q gain [ 54 ], although the number of cases studied was small. This unusual feature, along with the pattern of CGH alterations with a high proportion of changes at telomeres, may suggest an imperfect assay, particularly for ADH samples where material would have been limited.

Two other CGH studies each showed several copy number gains Table 1 ; however, the sample sizes were just two pure ADH [ 55 ] and three synchronous [ 56 ]. These genetic studies emphasize the difficulty in analyzing small numbers of cases with varying definitions of ADH, often leading to different conclusions. Nonetheless, despite individual small sample sizes, across all LOH and CGH studies, 16q loss remained the most common cytogenetic event in pure ADH, followed by 1q gain, with other loci being gained and lost at relatively lower and varying frequencies.

In addition, collectively these studies show that most pure ADH carry one or more large-scale cytogenetic abnormalities. The goal of these studies has been to establish whether ADH could be a genetic precursor to carcinoma and determine which type of carcinoma , and to evaluate whether genetic events are required for progression.

More recently, next-generation sequencing approaches have been applied, although only in small numbers of cases so far. For example, Newburger et al. Similarly, Weng et al. This analysis revealed considerable lineage heterogeneity and the authors suggested that the early neoplastic lesions and DCIS were not direct precursors of the co-existing IDC, but rather independent clonal proliferations of cells with a common ancestor.

Interestingly, they also found that some neoplasias showed a mixed-lineage origin, referring to the samples whose cells are geographically co-located but have originated from at least two genetically diverse lineages although often still sharing an ancient common ancestor. The accumulated somatic mutations of those samples could not be explained by a single lineage tree, suggesting existing high intra-individual genetic heterogeneity, which was also observed by Larson et al.

Given that genetic heterogeneity may be a bad prognostic feature in several tumor types [ 59 ], its detection in benign lesions could be relevant for patient management. These genetic studies to date support a role for ADH as a precursor of carcinomas identified in the same breast, but they do not explain the risk associated with ADH for the contralateral breast.

It has been noted in multiple studies that ipsilateral recurrence is most common almost twice that of contralateral in the first 5 years after ADH diagnosis; however, the long-term risk remains high for both breasts [ 7 , 9 ]. It is important to note that ipsilateral recurrence is not limited to the initial site of diagnosis of ADH and in cases where the carcinoma recurs at a different quadrant, it could be speculated that this would be non-clonal.

Indeed, this possibility is supported by Larson et al. ADH may therefore also be a marker of elevated risk not associated with clonal recurrence. These micro-environmental influencers could provide a possible explanation for the initiation of multiple breast lesions over long periods of time, their persistence, and their progression to carcinoma.

Studying the association of atypia with these characteristics could give an insight into identifying patients with a higher risk of recurrence. Interestingly, a very recent study showed no association between mammographic breast density and risk of recurrence in patients diagnosed with atypical hyperplasia [ 14 ]. Breast density, therefore, despite being a major indicator of an altered breast microenvironment, appears not to influence subsequent progression to carcinoma after ADH.

Similarly, higher BMI, early menarche, and smoking are not associated with a higher risk of developing invasive cancer after a previous breast benign biopsy [ 61 ]. Further study is needed to evaluate the different contributions of these factors for disease initiation as distinct from disease progression.

The role of the immune system has barely begun to be investigated as a factor controlling disease progression, but could well be crucial.

Early models of breast cancer development, which proposed a direct linear progression from normal epithelium to ductal hyperplasia to ADH to low-grade DCIS and then to low- or high-grade IDC, are now considered to be oversimplified [ 21 ]. Instead, distinct low- and high-grade multistep models of breast cancer progression have been hypothesized [ 21 ]. Studies of breast cancer stem cells also suggest that, apart from the claudin-low subtype, the cell of origin for the other intrinsic breast cancer subtypes may originate at different points along the luminal progenitor lineage [ 64 ].

It remains unknown if distinct precursors arise from these progenitors since many of the molecular alterations are not necessarily exclusive to each pathway. Where does ADH fit into this new paradigm?

On one side, Larson et al. However, at least two of the clonal cases studied by Larson et al. Several other systems for typing of DCIS have been proposed, including categorisation based on nuclear grade and necrosis [ 32 , 33 ]. Silverstein and colleagues [ 32 ] have grouped DCIS into high-grade, non-high-grade with necrosis, and non-high-grade without necrosis and found an association between the subtypes and local recurrence and disease-free survival [ 34 ].

The existing system for the classification of intraductal epithelial proliferations assumes a spectrum from usual epithelial hyperplasia through ADH and low-grade DCIS to high-grade disease.

Recently published work using comparative genomic hybridisation to investigate DCIS of the breast has prompted the proposal of a hypothetical model for the pathogenesis of DCIS, which recognises genetic lesions associated with particular morphological subtypes. It is likely that some of these new methods will form the basis of a revised system of classification in the future with an underlying molecular genetic basis while maintaining clinical relevance.

This article is the second in a review series on The diagnosis and management of pre-invasive breast disease — current challenges, future hopes , edited by Sunil R Lakhani. J Clin Pathol. Ellis IO, Pinder SE, Elston CW: A critical appraisal of existing classification systems of epithelial hyperplasia and in situ neoplasia of the breast with proposals for future methods of categorization: where are we going?. Semin Diagn Pathol. Breast Cancer Res Treat. Connolly JL, Schnitt SJ: Clinical and histologic aspects of proliferative and non-proliferative benign breast disease.

J Cell Biochem — Supplement. Cancer Epidemiol Biomarkers Prev. A forensic autopsy study. A long-term follow-up study. Cancer Causes Control. World J Surg. Tavassoli FA, Norris HJ: A comparison of the results of long-term follow-up for atypical intraductal hyperplasia and intraductal hyperplasia of the breast.

J Cell Biochem. Article Google Scholar. Hum Pathol. Google Scholar. Tavassoli FA: Intraduct hyperplasias, ordinary and atypical. Virchows Archiv. Rosai J: Borderline epithelial lesions of the breast. Am J Surg Pathol. Lagios MD: Duct carcinoma in situ. Pathology and treatment. Surg Clin North Am. Long-term follow-up after treatment by biopsy alone. Article PubMed Google Scholar.