Management of Lobular Neoplasia and Ductal Carcinoma in Situ

LCIS as a Risk Factor for Invasive Breast Cancer and Lobular Neoplasia

In the late 1970s the dominant belief that LCIS required therapeutic mastectomy was questioned when Haagensen at Columbia Presbyterian Hospital and Rosen at Memorial Sloan Kettering Cancer Center both independently began to advocate for less drastic management. In Haagensen’s series, 211 women with pure LCIS underwent excision alone and were followed for evidence of development of subsequent IBC. Of the women, 10% developed an ipsilateral breast cancer, and 9% were subsequently diagnosed with a contralateral invasive tumor. When occurring in the same breast, the invasive cancers were not always found at the original LCIS biopsy site. Haagensen argued that LCIS is better described as a risk factor than a preinvasive cancer because longitudinal series show IBC of either ductal or lobular histology developing in either breast with similar frequency. As a risk marker for cancer, bilateral mastectomy was felt to be overly aggressive and largely unnecessary in the setting of LCIS. Haagensen and colleagues reasoned that avoiding mastectomy was appropriate because of both the low incidence of subsequent breast cancer observed and the nearly equal hazard of contralateral breast cancer, which would be left unaddressed by a unilateral mastectomy.

Morphologic Features of Lobular Carcinoma in Situ

The histologic distinction between lobular and ductal neoplastic processes was initially based on location in the ductal-lobular system and differences in cytologic characteristics. In their original 1941 description, Foote and Stewart described LCIS as a proliferation of small, uniform, discohesive cells filling and often distending the acinar units within a lobule. In this classic form of LCIS, the nuclei are round and have indistinct nucleoli, uniform chromatin, and a distinctly monotonous, low-grade appearance with minimal mitotic activity ( Fig. 29.1 ). The lobular-based proliferation of LCIS is typically solid, without the architectural lumen formation typical of cribriform pattern DCIS. Lobular proliferations that fill and distend at least 50% of the acini in a lobule are classified as LCIS, whereas involvement of less than 50% of the acini is considered ALH ( Fig. 29.2 ). Because this definition of lobular distention can be subjective and the 50% threshold is somewhat arbitrary, some pathologists prefer the all-encompassing term lobular neoplasia , whereas others favor the separate terminology, arguing that it remains clinically useful because LCIS conveys a higher IBC risk than does ALH. Page and colleagues estimated that ALH conveys a four- to fivefold increased invasive cancer risk, whereas LCIS conveys a full ninefold increased risk in the absence of endocrine suppression.

LCIS can sometimes be difficult to differentiate from DCIS, especially when classic LCIS appears florid, with markedly distended lobules and foci of necrosis. Expression of the cell adhesion molecule E-cadherin is typically lost in LCIS and retained in DCIS, making immunohistochemistry staining for this marker useful in this differential ( Fig. 29.3 ).

Pleomorphic Lobular Carcinoma in Situ

There have been multiple descriptions of LCIS showing an in situ lobular pattern of growth similar to the classic LCIS form (see Fig. 29.1 ) but a high-grade, pleomorphic cytology that more resembles the aggressive phenotype of high-grade DCIS. Such lesions have been variably called pleomorphic LCIS ( Fig. 29.4 ). In contrast to the monomorphic cells of classic LCIS, pleomorphic LCIS cells have marked nuclear atypia, demonstrate variation in size, and have frequent to abundant mitotic activity. The pleomorphic form of LCIS more frequently contains central comedo necrosis, making its appearance strikingly similar to comedo-type high-grade DCIS. A molecular factor that distinguishes lobular from ductal pathology is the expression of E-cadherin, a cellular adherence protein that is present in ductal pathology but is absent in lobular disease. Histologic clues to this diagnosis include finding a discohesive appearance within a solid, high-grade in situ lesion, the presence of intracytoplasmic lumens, or the coexistence of classic LCIS. E-cadherin staining is often required for confirmation that the cells are lobular in origin. It has been speculated that pleomorphic LCIS may have an increased likelihood of being associated with ILC and, in particular, the pleomorphic ILC subtype that is known to be more biologically aggressive.

Clinical Features of Lobular Carcinoma in Situ

LCIS typically presents as an asymptomatic occult lesion incidentally discovered during histologic workup for another clinical or radiographic indication. Only rarely will LCIS present as a discrete lesion seen either by mammogram or ultrasound. It is even less common for lobular neoplasia to present as a clinically palpable mass. Most instances of LCIS are incidentally discovered on breast biopsy conducted for another reason. Although fewer than 5% of breast biopsies performed for benign conditions ultimately yield a diagnosis of LCIS, it is hypothesized that the true incidence may be much higher in the general female population because many women with lobular neoplasia remain undiagnosed as they have no other indication for breast biopsy. It is commonly widespread in the breast, with patterns that are multifocal, multicentric, and/or bilateral.

Risk of Subsequent Invasive Carcinoma After LCIS Diagnosis

Women diagnosed with LCIS are typically quoted to have an 8- to 10-fold increased lifetime risk for developing breast cancer in both the ipsilateral and the contralateral breast. The absolute risk of breast cancer after LCIS is 20% to 25% after 20 years. Mathematical modeling suggests that during the first 15 years after biopsy, women with LCIS have 10.8 times the risk of breast cancer development compared with women of comparable age who lack proliferative disease findings on breast biopsy. A more recent publication from Memorial Sloan Kettering Cancer Center examining 29 years of clinical surveillance reported a 15.8% rate of subsequent breast cancer development among 1060 women diagnosed previously with LCIS. The majority of the cancers were ipsilateral (63%), with 25% contralateral and 12% bilateral with both ductal and lobular invasive histology. Chemoprevention was the only factor found on multivariate analysis to influence breast cancer risk, substantially decreasing it. On average, they found a 2% annual incidence of breast cancer development in the setting of a prior diagnosis of LCIS.

In general, the risks of cancer in the ipsilateral and the contralateral breast are approximately equal, as shown in multiple longitudinal studies of patients diagnosed with LCIS by surgical biopsy ( Table 29.1 ). Multiple studies have attempted to provide more clarity on the upgrade rates of LCIS and ALH seen at core needle sampling and to delineate any correlation with the risk of identifying subsequent invasive disease ( Table 29.2 ). These study findings reveal a significantly higher upgrade rate associated with both florid and pleomorphic LCIS when compared with classic LCIS or ALH. Such findings have allowed the National Comprehensive Cancer Network (NCCN) screening and diagnosis panel to suggest that for individuals with classic LCIS on core sampling where the finding is concordant with breast imaging findings, surveillance alone is sufficient and surgical excision may not be necessary for definitive diagnosis. However, excision is recommended with pleomorphic or florid LCIS, given the higher likelihood of upgrade.

Chemoprevention of Invasive Breast Cancer

Based on the finding that LCIS signifies an increased risk of ipsilateral and contralateral breast cancer development, devising a systemic chemoprevention strategy is important in this patient population. Tamoxifen is a selective ER modulator (SERM) with both agonist and antagonist properties, and it is commonly used in the treatment of both early-stage and metastatic breast cancer. Tamoxifen has also been shown to decrease the risk of contralateral breast cancer in women receiving treatment in the adjuvant setting, and thus was chosen for evaluation in the prevention setting. Historically, four large randomized clinical trials evaluated the use of tamoxifen for breast cancer risk reduction. Two of these trials showed a statistically significant reduction in the incidence of IBC among women treated with 5 years of tamoxifen compared with those who received placebo. In the The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-01 prevention trial, there was a 49% reduction in the incidence of IBC ( P < 0.00001), whereas the International Breast Cancer Intervention Study (IBIS-I) showed a 27% reduction in risk among individuals taking the drug ( P = 0.004). Two additional trials reported smaller, nonsignificant decreases in breast cancer risk among tamoxifen-treated women, whereas a meta-analysis that combined results from all four trials showed a 34% to 38% reduction in breast cancer risk.

Only the NSABP P-01 trial specifically evaluated a subset of participants with LCIS. This trial enrolled 13,388 women at increased risk of breast cancer by virtue of an elevated Gail model score (5-year risk ≥1.66% of developing breast cancer), age greater than 60 years, or a past history of biopsy-proven LCIS or atypical ductal hyperplasia (ADH). Participants were randomized to tamoxifen (20 mg daily) versus placebo, for a planned duration of 5 years. Six percent of study participants had a history of LCIS, and an additional 9.1% of enrollees had a history of atypia. As noted earlier, a 49% reduction in breast cancer incidence was seen in the tamoxifen cohort. The relative risk of breast cancer was 0.44 (95% confidence interval [CI] 0.16–1.06) among women with a history of LCIS and 0.14 (95% CI 0.03–0.47) among women with a history of atypia. Importantly, no reduction was seen in the risk of ER-negative breast cancer, nor was a difference in overall survival noted between the two study arms. On the basis of the NSABP P-01 trial results, the US Food and Drug Administration (FDA) approved tamoxifen for breast cancer prevention.

Raloxifene is another SERM with a slightly different side effect profile. The Study of Tamoxifen and Raloxifene (STAR) trial, a head-to-head comparison of raloxifene to tamoxifen for breast cancer chemoprevention showed the two agents to be equivalent in terms of reducing the risk of IBC in postmenopausal women. It is important to note that although the NSABP P-01 trial included both pre- and postmenopausal women, only postmenopausal women were eligible for the STAR trial. Thus, although the STAR trial resulted in FDA approval for raloxifene for the indication of breast cancer risk reduction in postmenopausal women, tamoxifen remains the only FDA-approved agent for breast cancer chemoprevention in premenopausal women.

Aromatase Inhibitors for Chemoprevention

In clinical trials in the adjuvant treatment setting, aromatase inhibitors have been shown to be superior to tamoxifen in terms of their effect on contralateral breast cancer, leading to interest in investigating these agents in the prevention setting. The IBIS-II study enrolled postmenopausal women aged 40 to 70 at increased risk of breast cancer, including women with a history of LCIS, atypical hyperplasia (AH), or surgically treated DCIS, and randomized participants to anastrozole versus placebo for a period of 5 years. There were a total of 154 (8%) patients with LCIS/AH in the treatment arm, plus 190 (10%) with LCIS/AH in the placebo arm. Overall, there was a significant decrease in the number of breast cancers identified in the anastrozole group, and although it did not reach statistical significance, women with LCIS/AH and without prior hormone replacement therapy (HRT) exposure in the anastrozole cohort had an increased benefit and greater risk reduction than others in the study. These results were similar to the mammary prevention.3 (MAP.3) study, which enrolled postmenopausal women at least 35 years of age with increased risk of breast cancer based on either the Gail model or previous history of LCIS, AH, or DCIS. Women with atypia/LCIS accounted for 11% of the overall study participants. Study participants were randomized to either 5 years of exemestane (Aromasin) or placebo and stratified based on Gail score and current aspirin use. At 3 years’ follow-up, of 4560 patients enrolled, 11 cancers had developed in the treatment group and 32 in the placebo arm, and the superiority of exemestane to placebo was seen in all subgroups, including those with LCIS. The American Society of Clinical Oncology in 2019 updated their guidelines on chemoprevention for breast cancer, recommending tamoxifen for premenopausal women over the age of 35, as well as anastrozole, raloxifene, tamoxifen, or exemestane for use in postmenopausal females.

Surgical Excisional Biopsy Showing Lobular Carcinoma in Situ

Historical data indicate that lobular neoplasia is found in 0.5% to 4% of excisional biopsies and 1.5% of core needle breast biopsies. Typically, additional invasive intervention is not indicated when LCIS is diagnosed by surgical excision, even when the lesion is seen at the surgical margin. Because LCIS generally does not itself require surgical treatment, surgical biopsy showing LCIS should not itself demand further intervention, because surgical margins are not clinically relevant. Unlike surgical treatment for DCIS or invasive cancer, it is not necessary to surgically remove more breast tissue simply because the tissue that was excised had LCIS at the edge of the excision specimen. This conclusion is supported by a 2004 study of 40 patients with invasive cancer and associated lobular neoplasia. Although 14 of the patients had either close (<2 mm) or frankly positive margins for lobular neoplasia, none suffered local recurrence in the breast after a median of 67 months’ follow-up. Such results suggest that observation can safely replace excision when margins show LCIS involvement.

Core Needle Samples Showing Lobular Carcinoma in Situ

Percutaneous core needle biopsy is the sampling method now typically used for the primary evaluation of suspicious breast findings. Although the benefits of tissue sampling with this technique are established, needle biopsy has an inherent potential risk of sampling error or underestimation of malignancy owing to collecting smaller specimens than are obtained at surgery. Although the likelihood of pathologic upgrade has been extensively studied for ADH at core needle biopsy, it remains more controversial whether surgical excision is required when LCIS is the most severe histopathology result identified by core needle–biopsy sampling.

The 2021 NCCN breast cancer diagnosis and screening guidelines recommend high-risk screening of all patients found to have lobular neoplasia (LCIS/ADH) to begin at time of diagnosis, beginning at 25 years old. Recommendations include clinical examination every 6 to 12 months, annual screening mammogram beginning at age 30, and consideration of breast magnetic resonance imaging (MRI) beginning at age 25. The NCCN guidelines do acknowledge that multifocal/extensive LCIS may be associated with an increased risk of invasive disease being found at excision for classic LCIS. It seems reasonable, and is within the NCCN guidelines, to recommend excision for classic LCIS seen on core biopsy when there are discordant pathology and imaging findings, when the lesion is associated with additional atypical findings (ALH, ADH, flat epithelial atypia [FEA], etc.), when the lesion is extensive and/or involves more than four TDLUs, and when the classic LCIS is associated with a mass on imaging. Owing to the relatively high upgrade rate, surgical excision is generally recommended in the setting of pleomorphic LCIS.

Surgical Management of Pleomorphic LCIS/Margins

In the setting of pleomorphic LCIS, the NCCN recommends management along the breast cancer treatment pathway with 2 mm margins similar to margins for DCIS. Whereas there are no large, randomized trials evaluating margin status for patients with pleomorphic LCIS, several small retrospective studies have been conducted on the subject. A study from MD Anderson evaluated the implications of margin status in 26 patients with pleomorphic LCIS. Margins were grouped into pleomorphic LCIS at the margin, ≤1 mm from the margin, 1.1 to 2 mm from the margin, and >2 mm from the margin. Recurrence was identified in one patient who had a positive margin at time of resection. All other patients were disease-free at time of last follow-up. Thus the authors recommended obtaining negative margins (2 mm) in patients with pleomorphic LCIS. Another study from Memorial Sloan Kettering Cancer Center also recommended excision to negative margins, as all recurrences in their series occurred in patients with close (<1 mm) or positive margins. This study was limited owing to a small cohort size of 11 patients but it reports the longest follow-up for patients with pleomorphic LCIS treated with excision and chemoprevention. In 2018 Masannat and colleagues conducted a multicenter audit on pleomorphic LCIS, reviewing 176 cases. Study findings revealed that pleomorphic LCIS was associated with a high upgrade rate to invasive cancer, higher-grade tumors, and older age. The authors support the recommendation of excising pleomorphic LCIS with at least 2 mm margins, similar to DCIS. In 2018 a study from the Mayo Clinic by Desai and colleagues evaluated treatment outcomes in patients with pleomorphic LCIS diagnosed on core needle biopsy (n = 15) or excisional biopsy (n = 3). Of the 15 patients with pleomorphic LCIS on core needle biopsy, 3 (20%) were found to have invasive cancer on surgical excision. Among the 15 patients with final diagnosis of pure pleomorphic LCIS, there were two with ipsilateral recurrence, one of whom had a focally positive margin at time of segmental mastectomy. As such, the authors also concluded that excision with 2 mm margins for pleomorphic LCIS was best.

Breast Conservation in Patients Who Have LCIS Coincident With Invasive Cancer

In general, the presence of LCIS in conjunction with an invasive malignancy is not a contraindication for breast-conserving surgery (BCS) and reexcision is not indicated solely based on the presence of LCIS at a surgical margin. Controversy remains regarding management of surgical margins involved by pleomorphic LCIS. It is currently recommended that pleomorphic LCIS, like DCIS, should be excised with negative surgical margins; however, there is no clear consensus regarding management of pleomorphic LCIS margin involvement in the setting of concurrent invasive cancer, and each patient should be discussed individually.