The phrase “high-risk breast pathology” has two meanings. Classically, it refers to specific histologic findings in breast biopsy tissue that portend an increased risk of breast cancer for a woman in the years after the breast biopsy. With the shift in recent years from surgical excision of breast lesions to the routine use of percutaneous biopsy for diagnosis, high-risk breast pathology has also taken on a second meaning—breast lesions identified at percutaneous biopsy that may be malignant but are not adequately diagnosed with the percutaneous approach and therefore require surgical excision for definitive exclusion of malignancy. Thus, they are “high-risk” because they indicate a substantial risk that cancer is currently present in the breast at the needle biopsy site. Classic high-risk lesions with proven increase in long-term breast cancer risk include lobular carcinoma in situ (LCIS), atypical lobular hyperplasia (ALH), and atypical ductal hyperplasia (ADH). Other high-risk breast pathology lesions with less long-term risk but with concern for upgrade after needle biopsy include flat epithelial atypia, radial scar, and papillary lesions. This chapter will address both aspects of increased risk for these lesions—long-term increase in breast cancer risk as well as the risk of “upgrade” to cancer with surgical excision of the percutaneous biopsy site.

High-risk breast pathology refers to histologic abnormalities that confer an increased risk of breast cancer. The surgeon’s role in the clinical management of these lesions is twofold and includes (1) ensuring adequate diagnostic sampling of the lesion, and (2) recommending a strategy for long-term breast cancer surveillance and risk reduction that is tailored to the individual’s subsequent breast cancer risk. In the modern era of mammographically detected breast abnormalities and image-guided needle biopsies, some breast lesions are prone to underdiagnosis of cancer with a core needle biopsy approach. Surgeons need to understand which lesions require a surgical excision of the biopsy site in order to obtain adequate diagnosis of any malignancy that exists at that site. Once malignancy at the biopsy site is confidently ruled out, long-term clinical management of the patient depends on the level of breast cancer risk associated with the particular benign pathology identified. In general, patients with high-risk breast pathology are managed with surveillance and prevention strategies, but in some circumstances, surgical risk reduction may be considered. In this chapter, we review issues related to the diagnosis of high-risk lesions and recommendations for clinical management.

The “classic” high-risk breast lesions—lobular carcinoma in situ (LCIS), atypical ductal hyperplasia (ADH), and atypical lobular hyperplasia (ALH)—were identified years ago as having an increased future risk of breast cancer. In the 1970s, breast cancer risk after a diagnosis of LCIS was reported as approximately 1% per year, equally distributed across both breasts.¹ In 1985 Dupont and Page² reported on breast cancer risk for women after benign breast biopsies. Risk of breast cancer was compared to the general population risk and was stratified into three major histologic categories of benign findings: (1) nonproliferative disease includes fibroadenomas, cysts, and apocrine metaplasia (relative risk (RR) of about 1.2), (2) proliferative disease without atypia includes benign papillary lesions, usual duct hyperplasia, radial scar, sclerosing adenosis (RR of about 1.8), and (3) atypical hyperplasia includes either ADH or ALH (RR of about 4).² These findings, and specifically stratification of breast cancer risk based upon the specific histologic features of the breast tissue, were corroborated by other groups,^3,4 as well as more recent studies of women with benign breast disease.^5,6 In 1998, the successful report of tamoxifen for breast cancer prevention further advanced awareness of high-risk breast lesions,⁷ highlighting both the need to identify women at increased risk and new possibilities for risk reduction.

Percutaneous Biopsy

The shift to percutaneous core needle biopsy in the 1990s led to new concerns in the diagnosis and management of breast lesions, leading to the designation of certain breast lesions as being “high-risk” for underestimation (or missed diagnosis of malignancy).⁸ Appropriate concern was given to the limitations of the percutaneous needle biopsy technique, as there are several reasons that can explain underestimation of cancer with a percutaneous needle biopsy approach. First, the targeted lesion can be completely missed—fortunately a rare occurrence. However, it is common that only a portion of the lesion is removed, introducing the possibility of sampling error.⁹ Furthermore, even if the lesion is removed completely, the lesion is usually fragmented into multiple small pieces, which increases the difficulty in making a definitive histologic diagnosis.¹⁰ Multiple studies have shown that extent of tissue sampling by needle biopsy is related to frequency of missed cancer diagnosis, with higher upgrade rates for smaller-gauge biopsy needles (i.e., 14G needle vs. 11G vacuum-assisted biopsy devices) and larger mammographic lesions.^11–13 These issues highlight the importance of concordance between the radiologic findings and pathologic findings on core biopsy in order to minimize the possibility of missed malignancy and to understand which lesions on core needle biopsy should be surgically excised. When surgical excision is undertaken, the goal is to remove the biopsy site and the original imaging lesion that led to the core needle biopsy in order to rule out the presence of an existing malignancy.

Radiologic-Pathologic Concordance

Radiologic-pathologic concordance is required in current practices that perform percutaneous needle biopsy, whether the biopsy is guided by palpation or by imaging.^14,15 The combined assessment of clinical, imaging, and pathologic findings that are all internally consistent is referred to as concordance. The surgeon is an important part of the multidisciplinary team that characterizes modern breast care and should contribute to the concordance assessment of breast core needle biopsy results.^16–19 Concordance assessment requires review of the original diagnostic mammograms demonstrating the abnormality, and also the post-biopsy imaging, in order to assess whether the biopsy marker is located at the site of the original lesion. The histologic findings as described by the pathologist are then interpreted in the context of the clinical and imaging findings to determine if they are all in agreement. Ideally, concordance determination is performed with input from the radiologist, pathologist, and the surgeon. Surgical excision is indicated if findings are discordant or if there is concern that the target lesion was not sampled adequately. In general, surgical excision should be performed for a core needle biopsy demonstrating atypia or a papillary lesion in the presence of a palpable or imaging mass lesion. Specific recommendations for surgical excision will be discussed separately for each high-risk lesion.

Background

Lobular carcinoma in situ is a proliferation of small, bland-appearing monomorphic epithelial cells with small nuclei that fill and distend at least half the acini of a lobular unit.²⁰ When present to a lesser degree the lesion is designated as ALH (see below). LCIS and ALH represent changes of varying severity along the spectrum of lobular neoplasia. The term LCIS was suggested in 1941 by Foote and Stewart, observing this lesion in 14 of 300 cancerous mastectomy specimens.²¹ The authors judged that LCIS was a direct precursor to invasive lobular carcinoma and therefore recommended that it be treated with mastectomy. Years later, reports in the 1970s showed that women with LCIS have similar risk of cancer in both breasts, and subsequent cancers included invasive ductal tumors as well as invasive lobular cancers^1,21–23. Histologically, LCIS is often multicentric and bilateral.^1,21–23 Thus LCIS became considered a marker of increased risk rather than a true precursor lesion.

Epidemiology

Lobular carcinoma in situ is usually discovered as an incidental finding in a breast biopsy performed for another reason. For this reason, the incidence of LCIS in the general population is difficult to ascertain. Population-based data from the Surveillance, Epidemiology, and End Results (SEER) registry (1978 to 1998) show an incidence of 3.19 per 100,000 women.²⁴ In contrast to population-based data, LCIS appears to be more frequent (about 4%) among women with clinical abnormalities in series of benign breast disease.^1,22,23

Breast Cancer Risk

Women with LCIS have an eight- to tenfold relative risk of breast cancer compared to the general population,²⁵ and several studies have shown that this risk is fairly even across a woman’s lifetime, averaging about 1% per year.^26,27 In a more recent report of 776 patients with LCIS from Memorial Sloan Kettering Cancer Center, 13% of women developed cancer at 58 months, suggesting that risk in women with LCIS is about 2% per year, higher than previously estimated.²⁸ In addition, LCIS serves as a high-risk marker for both breasts, with similar frequency of cancer in both the breast undergoing biopsy and the contralateral breast.²⁹ Bodian et al³⁰ reported the following absolute frequencies of either DCIS or invasive cancer in a series of women with LCIS: 13% at 10 years, 26% at 20 years, and 35% at 35 years. Due to the increased risk of future breast cancer associated with LCIS, bilateral mastectomy has been performed in some women historically, but current management recommendations favor prevention medications and surveillance rather than surgical risk reduction.³¹ Thus, a diagnosis of LCIS made by surgical excision does not require further surgical intervention, although some women may choose to pursue bilateral mastectomy for maximal risk reduction (after careful counseling).

Excision After Core Needle Biopsy

When LCIS is diagnosed on core needle biopsy, it is controversial whether surgical excision should be performed in order to exclude concurrent malignancy at the biopsy site. Published studies from 1999 to 2008 demonstrate that upgrade rates after LCIS on core biopsy range widely, from 0% to 60%.^25–34 There are some common limitations among these published studies that may explain the widely variable findings: (1) not all cases of LCIS on core biopsy underwent excision, (2) studies vary on whether they exclude cases with radiologic-pathologic discordance, and (3) LCIS may not have been the only histologic finding prompting surgical excision. These factors result in selection bias and differences in the probability of finding a cancer at the biopsy site.

A few recent studies have reported low upgrade rates in favorable cases of isolated lobular neoplasia, that is, no other high-risk lesions and no radiologic-pathologic discordance.^32,33 Rendi et al³² reported an upgrade rate of 4% following surgical excision of 68 cases of LN on core biopsy, and similarly Murray et al³³ reported an upgrade rate of 3% following surgical excision of 72 cases of concordant LN on core biopsy. In both of these series, the cancers identified were small, low-grade malignancies.^32,33 A third series reported by Shah-Khan et al³⁴ showed an upgrade rate of only 1 out of 20 cases of lobular neoplasia that had radiologic-pathologic concordance. Although these series are retrospective and subject to selection bias, they represent the most careful reviews of this clinical scenario to date and suggest that routine excision may not be needed for all cases of LCIS on core biopsy when radiologic-pathologic concordance is confirmed.

Long-term Management of LCIS

When concurrent malignancy is confidently excluded, next steps in management for women with LCIS include counseling regarding (1) their future breast cancer risk (described above), and (2) options for risk reduction. The prospective randomized trial of tamoxifen versus placebo in the National Surgical Adjuvant Breast and Bowel Projected (NSABP) Breast Cancer Prevention Trial (BCPT, P-1) demonstrated that tamoxifen decreases the risk of invasive breast cancer by approximately half.⁷ The subsequent NSABP Study of Tamoxifen and Raloxifene (STAR, P-2) demonstrated that raloxifene is equivalent to tamoxifen in reducing invasive breast cancer risk.³⁵ Women with LCIS were included in these studies (6.2% of 13,338 participants in the P-1 trial, and 9.2% of 19,747 participants in the STAR trial). Most recently, both exemestane and anastrozole have also been evaluated for prevention of breast cancer in postmenopausal women.^36,37 Similar to tamoxifen and raloxifene, these agents reduced breast cancer risk by approximately half in all women. In both of these recent studies, women with LCIS and atypical hyperplasia were grouped together for analysis and constituted about 8% of both clinical trials. Among the subgroup of women with LCIS or atypical hyperplasia, anastrozole resulted in a 69% reduction in breast cancer events.³⁷ In this same high-risk subgroup exemestane appeared somewhat less effective with risk reduction of 39%.³⁶

For women who choose not to pursue preventive medications, close surveillance is recommended to enhance early detection. This should include annual clinical breast exam and screening mammography.³⁸ Use of breast MRI screening for early detection has been controversial. MRI is the most sensitive imaging modality for detection of breast cancer but has a high false-positive rate,³⁹ and American Cancer Society guidelines indicate that there is insufficient evidence to recommend for or against use of MRI for early detection in women with LCIS.⁴⁰ In a recent retrospective study of women with LCIS, MRI screening was not associated with increased breast cancer detection or earlier stage at diagnosis.²⁸

With effective risk-reduction medications, surgical risk reduction with bilateral mastectomy is now uncommon for women with LCIS. A recent study found that LCIS was the indication for bilateral prophylactic mastectomy in only 7% of cases.⁴¹ However, surgical risk reduction remains an option for women with LCIS and may be further motivated in women with LCIS who do not tolerate prevention medications or who have a strong family history. Bilateral mastectomy for risk reduction reduces breast cancer risk by about 90% to 95% but does not remove all chances of a future breast cancer that could occur in the region of the prior breast.⁴² Furthermore, there is no evidence to date indicating that bilateral risk reduction mastectomy prolongs survival. Therefore, women contemplating bilateral prophylactic mastectomy should undergo lengthy and careful counseling of the risks and benefits of this irrevocable choice, including significant but imperfect reduction in breast cancer risk and possible detrimental impact on quality of life, body image, and sexual function.⁴³ Therefore, careful discussion of risks and benefits is recommended in an unhurried timeframe.