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Abstract

During the last several years, increased public awareness, advances in breast imaging and enhanced screening programs have led to early breast cancer detection and attention to cancer prevention. The number of image-detected biopsies has increased, and pathologists are expected to provide more information with smaller tissue samples. These biopsies have resulted in detection of increasing numbers of high-risk proliferative breast disease and in situ cancers. The general hypothesis is that some forms of breast cancers may arise from established forms of ductal carcinoma in situ and atypical ductal hyperplasia, and possibly from more common forms of ductal hyperplasia. However, this is an oversimplification of a very complex process given the fact that the majority of breast cancers appear to arise de novo or from a yet unknown precursor lesion. Currently, atypical ductal hyperplasia and ductal carcinoma in situ are considered as morphologic risk factors and precursor lesions for breast cancer. However, morphologic distinction between these two entities has remained a real issue that continues to lead to overdiagnosis and overtreatment. Aside from morphologic similarities between atypical ductal hyperplasia and low-grade ductal carcinoma in situ, biomarker studies and molecular genetic testing have shown that morphologic overlaps are reflected at the molecular level and raise questions about the validity of separating these two entities. It is hoped that as we better understand the genetic basis of these entities in relation to ultimate patient outcome, the suggested use of the term ‘borderline breast disease’ can minimize the number of patients who are subject to overtreatment.

Keywords

atypical ductal hyperplasia borderline breast disease borderline breast lesion breast cancer breast cancer precursor breast cancer risk factor proliferative breast disease screening mammography

Improved understanding of the biology of breast cancer in the last several years has resulted in a paradigm shift in diagnosis and therapy. Advances in breast imaging, emphasis on screening mammography and increased public awareness have contributed to increased detection of a variety of high-risk proliferative breast diseases, carcinoma in situ and small invasive cancers [1 –5]. Open surgical biopsies have been replaced by minimally invasive sampling procedures such as fine-needle aspiration cytology and core needle biopsy [6,7]. In addition, breast conservation therapy and sentinel lymph node biopsy have become the preferred surgical alternatives to mastectomy and complete axillary lymph node dissection [8,9]. Furthermore, molecular targeted therapy has provided opportunities for novel, effective and individualized cancer therapy [10,11].

More importantly, these advances have contributed to a significant change in the fundamental concept of delivery of care to patients with breast cancer. Integrated care through a multidisciplinary approach has been widely recognized by different disciplines, healthcare providers and patient advocates, and has led to the establishment of a large number of breast centers across the globe [12]. These changing trends, however, have brought different levels of responsibilities to physicians to better stratify patients for therapy on the basis of the extent and the biology of their disease.

Pathologists have played a central role in the realization of the aforementioned progress. Pathology is the study of human illness, and pathologists carry the heavy burden of rendering an accurate diagnosis and providing appropriate prognostic/predictive information. Pathologists offer the last word about the nature of a disease and define the course of therapy on an individual basis. If these tasks are not performed properly, the clinicians are misled and the patients will subsequently suffer from the wrong treatment.

The current practice of breast pathology is complex and requires integration of morphology with clinical presentations and breast imaging, and takes into consideration the age and risk factors of each patient. Morphologic features that are used for pathologic diagnosis of surgically excised lesions and mastectomy specimens may no longer be successful for rendering a life-changing diagnosis on the small sample sizes that are currently obtained by image-detected biopsies. In addition, there is still significant inter-and intraobserver variations among pathologists in interpretation of atypical proliferative lesions and low-grade carcinomas [13 –18].

This article is designed to provide a summary of diagnostic issues related to sampling and accurate diagnosis of atypical ductal hyperplasia (ADH) and low-grade ductal carcinoma in situ (DCIS). This is followed by a discussion about the rationale behind the suggested use of the term ‘borderline breast disease’ instead of DCIS.

Sampling issues

Correlation of pathology with breast imaging

Image-detected minimally invasive sampling procedures are currently utilized for diagnosis of breast lesions. Fine-needle aspiration cytology is suitable for assessment of palpable breast lesions and in aspiration of breast cysts. Core needle biopsy is the preferred procedure for nonpalpable breast lesions [6,7]. Regardless of the type of procedure, both fine-needle aspiration cytology and core-needle biopsy provide an excellent opportunity to avoid unnecessary open biopsies. These procedures have similar diagnostic and sampling issues, and it is incredibly important to use the right procedure for each patient based on clinical/imaging presentations. There has to be a clear understanding of the remote possibility that the sampled tissue examined under the microscope may not represent the abnormality detected by imaging. This requires close and effective communication between the radiologists and the pathologists [19]. In addition, there are a number of entities in breast pathology diagnosed by minimally invasive procedures that require follow-up surgical excision of the entire lesion to further characterize the nature and extent of the disease [19].

These entities include ADH, lobular neoplasia, as well as mucinous, sclerosing and fibroepithelial lesions. Diagnosis of DCIS by core-needle biopsy has been shown to be associated with evidence of invasive cancer in the subsequent lumpectomy or mastectomy specimen in up to 20% of cases [19]. Distinction between complex sclerosing lesions and tubular carcinoma, the status of invasion suggested by displacement of epithelial cells during core needle biopsy, and the differentiation between usual ductal hyperplasia and ADH many benefit from the use of immunostains for myoepithelial cell markers and high- and low-molecular-weight keratins [20,21].

Diagnostic issues

Correlation between morphology & biology

The association between the degree of ductal proliferation and the subsequent risk for breast cancer development has been recognized for many years. The prognostic significance of the spectrum of morphologic features of proliferative breast lesions, including usual ductal hyperplasia, ADH and DCIS, have been described. It is generally agreed that usual ductal hyperplasia carries minimal or no increased risk for breast cancer, and does not require any additional follow-up surgical procedure [22].

By contrast, ADH and DCIS progress to invasive carcinoma in 4–5 and 8–10% of cases, respectively [22,23]. ADH is regarded as a morphologic risk factor for the development of breast cancer in either breast and requires no follow-up surgical/radiation therapy. It may, however, benefit from appropriate risk assessment and possible hormone therapy with tamoxifen. In 1998, the Tamoxifen for Prevention of Breast Cancer Report of the National Surgical Adjunct Breast and Bowel Project P-1 study showed the value of tamoxifen as a chemopreventive agent in women in high-risk groups. This study showed that administration of tamoxifen reduced the risk of invasive and noninvasive breast cancer by almost 50% and atypical hyperplasia by 86% [24]. This information underscores the significance of accurate diagnosis of ADH from usual ductal hyperplasia in designing follow-up strategies for risk reduction modalities.

Recognized as a breast cancer precursor, DCIS is a representation of clonal expansion of monomorphic epithelial cells within the ductal system. However, the differences in the morphology and biology of different forms of DCIS is a limiting factor in prediction of the rate of progression of DCIS to an invasive cancer. Currently, DCIS is classified based on the pattern of architectural presentation, nuclear features and the presence or absence of necrosis [23,25]. Current available scientific evidence indicates differences in genetic composition of low- and high-grade DCIS [26 –30]. These differences are responsible for differences in biology and outcome of different forms of DCIS. High-grade DCIS has the potential of rapid progression into an invasive form of breast cancer and is easy to diagnose. On the other hand, low-grade DCIS is a slow growing lesion that may ultimately progress into low-grade invasive cancer over a long period of time [26 –30]. There is also an association between low-grade DCIS, ADH and lobular neoplasia. This concept contradicts the current concept of considering DCIS to be completely separate from lobular neoplasia [25,26].

Regardless of different morphologic features and biologic behavior, the diagnosis of DCIS is followed by surgical intervention ranging from lumpectomy with radiation therapy to mastectomy with sentinel lymph node biopsy [29]. Without confirmatory tissue biopsy, the frequent use of MRI in newly diagnosed breast cancer patients may lead to false interpretation of benign entities as evidence of multifocal/multicentric DCIS. This practice leads to unnecessary mastectomy for a single small breast cancer with no other associated malignancy detected.

There is no doubt that the distinction between ADH and DCIS is incredibly important to reduce the impact of over- and under-treatment [31]. An article recently published in the New York Times displayed the seriousness of overdiagnosis of DCIS and received significant attention [32]. In this article, a few patients who had undergone cancer therapy for overdiagnosis of DCIS shared their stories about the impact of these errors on their lives both physically and psychologically. These stories brought public attention to the issues that have been known to the medical community for a long time.

In 1991, Rosai, one of the most distinguished surgical pathologists of our time, highlighted the significance of interobserver variability among experienced breast pathologists. In his report, Rosai showed no agreement among cases seen by five experienced pathologists [15]. Since then, other studies have reported significant inter- and intraobserver variability among academic and community pathologists [13 –18]. The results reflect the challenge of achieving agreement in interpretation of results. Even by providing training slides and following specific criteria, Schnitt et al. reported only 58% agreement among the participating pathologists [16]. To date, there has been no controlled study to provide reliable statistics regarding the frequency of under- and overdiagnoses. Currently, there is no mechanism for self-reporting of the errors in breast pathology and the fear of medicolegal issues limits the ability to conduct a meaningful assessment of the gravity of the problem [31,33,34].

Clinical implications

Under- & overtreatment

The reported inconsistencies regarding appropriate diagnosis of atypical proliferative change in breast pathology raises serious concerns regarding the robustness of the current diagnostic criteria. Currently, there is no consensus about the terminology that should be used to better define the biology of the spectrum of prognostically relevant proliferative changes in breast pathology. There is no single morphologic criterion or biomarker that can reliably identify patients who may develop breast cancer [35]. The currently used risk stratification modules and statistics are only a reflection of the science of probabilities. The proposed concept of progression of normal epithelial cells to hyperplasia, atypical hyperplasia, carcinoma in situ and, finally, an invasive cancer is an oversimplification of the complex process of tumorigenesis in breast cancer.

Current scientific evidence based on morphologic and biologic studies indicate the presence of an association between some precursor lesions with low nuclear grade breast carcinoma [25,26]. These entities include columnar cell lesions, lobular neoplasia, ADH and low-grade DCIS with invasive tubular carcinoma, tubulo-lobular carcinoma and classic lobular carcinoma. These entities have relatively favorable prognosis because of the high level of differentiation, which may be the result of the presence of fewer genetic aberrations [25,26]. Tarek et al. suggested that these lesions are members of a single family of low-grade precursors [36]. Evidenced by remarkably similar immunophenotypic characteristics, this phenotype is distinct from that seen in high-grade breast carcinomas.

Given that the morphologic and biologic features of ADH and low-grade DCIS are similar, and that these lesions represent a family of precursors that are of low malignant potential, it may be appropriate to use the term of ‘borderline breast disease’ for these entities. This change is particularly important in assessment of tissue samples obtained by core-needle biopsy that are challenged by the inherent tissue fragmentation and small sample size. These patients can be followed-up with complete surgical excision of the lesion. This approach provides an opportunity to examine the extent of the abnormalities seen in the larger tissue sample and to evaluate the biologic significance of those atypical entities. In the absence of any unexpected high-grade breast cancer, the patients with borderline lesions can be spared the anxiety associated with the term DCIS and be followed by close surveillance [37]. In addition, these patients do not have to experience the challenges associated with DCIS regarding their health and life insurance, and employment.

Efforts must be made to refrain from the use of the term carcinoma if there is any doubt about the diagnosis. The term ‘carcinoma’ carries a negative connotation for both patients and physicians. The fear of cancer paralyzes patients, particularly those that have a strong family history of cancer. The patients often give up too soon and resort to drastic therapeutic measures that may not be necessary. Similarly, the term ‘in situ cancer’ may have a different significance for each physician based on the pattern of their clinical practice, which may potentially lead to overtreatment.

Ideally, designing well-controlled prospective studies to monitor the morphologic and biologic characteristics associated with progression of normal mammary epithelial cells into malignant lesions provides the best resolution to these conflicts. However, in reality, it is incredibly difficult to convince a patient with the diagnosis of DCIS not to undergo the standard cancer therapy and to participate in a clinical trial. It is also not possible to expect asymptomatic individuals to undergo repeated tissue biopsy for the purpose of contribution to breast cancer research. For the time being, maintaining the term ‘DCIS’ for high-grade lesions and careful use of the term ‘borderline breast disease’ for low-grade DCIS may provide an alternative to minimize overdiagnoses and overtreatment [33,37].

Currently, the diagnosis of low-grade DCIS is followed by standard cancer therapy. Changing the term of low-grade DCIS to borderline breast disease results only in total excision of the entire abnormality observed clinically or by imaging, and close follow-up. This approach will eliminate cancer therapy. Retrospective analysis of cases of DCIS that have been misdiagnosed as benign lesions and were not completely excised have shown evidence of progression of these lesions into invasive breast cancer. These tumors have been low grade in nature and have occurred for up to 30 years in the same region as the biopsy site [27 –30]. Thus, downgrading of the term low-grade DCIS into borderline breast disease may result in the same consequences. If undetected and not resected, there is a remote chance of progression of low-grade DCIS into cancer.

However, it should be acknowledged that the aforementioned progression of DCIS into an invasive cancer may not have occurred if the original lesions have been completely excised to assure that no residual lesion is left behind. Thus, our suggested follow-up management of total surgical excision of the lesion should eliminate progression into cancer. In addition, keeping her breast for over 30 years is a lifetime comfort for women compared with losing their self-image by undergoing unnecessary and premature cancer therapy.

The proposed concept of changing the term ‘low-grade DCIS’ to ‘borderline breast disease’ is similar to the process of changing terminology of cervical carcinoma in situ to high-grade squamous intraepithelial lesion. Introduced by Papanicolaou as a numerical system for reporting cervical smears, it was recognized that this system is not used uniformly across different laboratories, and descriptive terms such as carcinoma in situ and dysplasia appeared in the reports of cervicovaginal cytology [38]. In the 1960s, Richart challenged the predictive significance of separating carcinoma in situ and dysplasia, and proposed a new term ‘cervical intraepithelial neoplasia’, designated as CIN1, CIN2, and CIN3 based on the degree of morphologic abnormalities [38]. However, for many years, squamous precursors were treated as much on the basis of the extent of disease and its location as their grade. It was only in 1989, when the Bethesda System of cervicovaginal cytology reporting introduced the term ‘squamous intraepithelial lesion’, which subdivides the disease into only two grades (low and high) based on the evolving understanding of the association with human papilloma virus infection and their progression to invasive cervical squamous cell carcinoma [39]. It is now generally agreed that most low-grade squamous intraepithelial lesions are, in fact, transient human papilloma virus infections that carry little risk of development of invasive squamous cell carcinoma, whereas most high-grade squamous intraepithelial lesions are associated with persistent human papilloma virus infection and have significant potential for progression to invasive cancer. These changes have influenced practice of gynecologic oncology and have made a positive impact on optimal patient care [40].

The future progress in molecular pathology and molecular breast imaging will provide opportunities for meaningful stratification of patients with borderline breast disease that may never progress to breast cancer. This approach will spare many patients from the emotional challenges associated with the use of the term DCIS and any unnecessary therapy. Recognition of breast pathology as an integral part of the building blocks for delivery of high-quality breast care and establishment of uniformity in diagnostic terminology among pathologists will ultimately influence the change.

Conclusion & future perspective

It is generally agreed that there is no current consensus regarding the morphologic criteria that should be adapted and how they should be applied for the distinction between ADH and low-grade DCIS. This distinction may be improved when it is possible to relate these entities to specific genetic and biochemical markers and correlate the findings with patient outcome. Future advances in genomic pathology and molecular imaging will serve as guiding lights to better understand the biology of these morphologic risk factors/precursor lesions. More importantly, attention to comparative effectiveness and accountability about the choice of screening, tissue sampling and follow-up management in breast cancer will hopefully balance therapy with the extent and biology of the spectrum of borderline breast disease.

Executive summary

During the last several years, there have been significant changes in the delivery of breast healthcare.

Fragmented care has been replaced by integrated team-based and patient-focused practice.

Pathologists have played a major role in contributing to the practice of personalized breast healthcare.

Screening mammography and image detected biopsy have increased the number of high-risk atypical proliferative lesions and ductal carcinoma in situ (DCIS) diagnosed.

The association between atypical proliferative lesions/DCIS and increased risk for breast cancer development is now an established fact.

There is significant inter- and intraobserver variability among pathologists in diagnosis of atypical ductal hyperplasia and low-grade DCIS.

There is no consensus among pathologists on the criteria that should be adopted and how they should be applied for the distinction between the aforementioned entities.

Low- and high-grade DCIS are genetically different forms of breast cancer precursors.

Low-grade DCIS is an indolent lesion.

High-grade DCIS is an aggressive lesion capable of rapid progression to invasive cancer and early metastasis.

Currently, the term DCIS is followed by cancer therapy regardless of the biology of the tumor.

The current diagnostic challenge between atypical ductal hyperplasia and low-grade DCIS continues to result in overtreatment.

The use of the term of ‘borderline breast disease’ instead of low-grade DCIS reduces the chance of overdiagnosis and spares many patients from unnecessary cancer therapy.

Footnotes

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Why the Term ‘Low-Grade Ductal Carcinoma in Situ’ should be Changed to ‘Borderline Breast Disease’: Diagnostic and Clinical Implications

Abstract

Keywords

Sampling issues

Correlation of pathology with breast imaging

Diagnostic issues

Correlation between morphology & biology

Clinical implications

Under- & overtreatment

Conclusion & future perspective

Footnotes

References