Abstract
Background:
The clinical significance of non-classic lobular carcinoma in situ (NC-LCIS) at the surgical margin of excisions for invasive cancer is unknown. We sought to determine if NC-LCIS at or near the margin in the setting of a concurrent invasive carcinoma is associated with risk of ipsilateral breast tumor recurrence (IBTR) and locoregional recurrence (LRR).
Methods:
Patients with stage 0-III breast cancer and NC-LCIS who underwent lumpectomy between 1/2010–1/2022 at a single institution were retrospectively identified. NC-LCIS margins were stratified as <2mm, ≥2mm, or within shave margin. Rates of IBTR and LRR were examined.
Results:
511 female patients (median age 60 years [IQR 52–69]) with NC-LCIS and an associated ipsilateral breast cancer with a median follow-up of 3.4 years [IQR 2.0–5.9] were identified. Final margins for NC-LCIS were ≥2 mm in 348 patients (68%), <2 mm in 37 (7.2%), and within shave margin in 126 (24.6%). Crude incidence of IBTR was 3.3% (n=17) and that of LRR was 4.9% (n=25). There was no difference in the crude rate of IBTR by NC-LCIS margin status (IBTR rate: 3.7% ≥2mm, 0% <2mm, 3.2% within shave margin, p=0.8) nor in LRR (LRR rate: 4.9% ≥2mm, 2.7% <2mm, 5.6% within shave margin, p=0.9).
Conclusions:
For completely excised invasive breast cancers associated with NC-LCIS, extent of margin width for NC-LCIS was not associated with a difference in IBTR or LRR. These data suggest that the decision to perform re-excision of margin after lumpectomy should be driven by the invasive cancer, rather than the NC-LCIS margin.
Keywords: lobular carcinoma in situ, breast cancer, lumpectomy, margin width, local recurrence, ductal carcinoma in situ, re-excision
INTRODUCTION
Classic-type lobular carcinoma in situ (LCIS), a proliferation of atypical cells that predominantly involve the terminal duct lobular units of the breast, was once thought to be a premalignant condition requiring excision. More recently, studies have demonstrated a very low upgrade rate to invasive carcinoma or ductal carcinoma in situ (DCIS) of less than 5%, for patients undergoing excision for classic type LCIS.1–7 Given this low upgrade rate, routine excision of clinical/radiographic concordant classic type LCIS is no longer performed and the finding of classic type LCIS at or near the margin of an invasive cancer excision does not necessitate re-excision.
Non-classic LCIS (NC-LCIS) subtypes, namely pleomorphic LCIS and florid LCIS, are also characterized by a proliferation of atypical discohesive cells. Unlike classic LCIS, pleomorphic LCIS is characterized by marked nuclear pleomorphism while florid LCIS displays similar cytomorphology to classic LCIS but with marked distension of the acini.8,9 NC-LCIS identified in a breast biopsy has a higher rate of upgrade to invasive cancer or DCIS, 20–65%, compared to classic type LCIS.10–16 In light of this higher upgrade rate, surgical excision for pure NC-LCIS found on core biopsy is routinely recommended, with negative margins preferred, although no association with worse recurrence based on margin status has been seen in small retrospective studies.17
However, when a lumpectomy is performed for invasive cancer or DCIS associated with NC-LCIS, there are currently no guidelines for appropriate margin width of the NC-LCIS.18 As a result, there is wide variability among breast surgeons in how margins for NC-LCIS are managed. A survey of breast surgeons found that 53% of surgeons do not recommend re-excision for pleomorphic LCIS, whereas 23% sometimes recommend re-excision and 24% always re-excise margins for pleomorphic LCIS.19 The absence of data on the association between risk of local recurrence and NC-LCIS margin status is likely the reason for the wide variability in surgeon practice. We therefore sought to determine if NC-LCIS at or near the margin in the setting of a concurrent invasive carcinoma or DCIS is associated with risk of ipsilateral breast tumor recurrence (IBTR) and locoregional recurrence (LRR).
METHODS
Consecutive patients treated at Memorial Sloan Kettering Cancer Center (New York, NY, USA) between 1/2010–1/2022 were retrospectively identified using a pathology database. Patients were included if they underwent lumpectomy for DCIS or stage I-III invasive cancer and had NC-LCIS. NC-LCIS was classified as pleomorphic, florid, with necrosis, or with pleomorphic features in either the initial biopsy or the lumpectomy specimen.14 Cases defined as acinar were classified as florid. Non-classic features, including large cell and signet ring, which are not classified as specific LCIS variants at this time were categorized as other. Patients undergoing mastectomy, those with metastatic disease at the time of diagnosis, prior ipsilateral breast cancer, or margins positive for invasive carcinoma or DCIS were excluded.
After obtaining Institutional Review Board (IRB) approval, clinical and pathologic variables were abstracted from the electronic medical record. Variables collected included age, race, ethnicity, invasive histology, type of NC-LCIS, extent of axillary surgery, number of margin re-excisions and reason for re-excision, pathologic T and N stage, tumor grade, estrogen receptor (ER), progesterone receptor (PR) and HER2 status, receipt of chemotherapy, radiation and endocrine therapy, as well as duration of endocrine therapy. Compliance with endocrine therapy was defined as either having completed 5 years of therapy or as being on endocrine therapy at the point of last follow-up. All data collection and storage were performed in accordance with IRB regulations.
Primary outcomes examined were crude rates of IBTR and LRR. IBTR was defined as any recurrent DCIS or invasive breast cancer within the same breast. LRR was defined as IBTR with or without regional nodal recurrence or regional nodal recurrence alone.
Margins were stratified as NC-LCIS <2 mm (including those with NC-LCIS documented on ink), ≥2mm, or within shave margins. It is routine practice at our institution to perform margin assessment with the cavity shave method.20 Cavity shave margins are sent separately from the lumpectomy specimen and it is from the shave margin that the final margin status is obtained. Patients were categorized as either <2mm or ≥2mm if an exact NC-LCIS margin distance was provided within the pathology report. As the World Health Organization classification of variants of LCIS evolved over the study period9, and as reporting guidelines for NC-LCIS margins are not standardized, there were patients in our cohort in whom no exact distance from margin for the NC-LCIS was provided. If no exact distance was described, but no NC-LCIS was present within the shave margin, patients were categorized as having ≥2mm margins. If there was NC-LCIS within the shave margin without an exact distance provided in the pathology report, patients were categorized in a third separate category, referred to as “within shave margin”.
Statistical analyses were performed using R 4.2. Comparison of descriptive characteristics was performed using Kruskal Wallis Rank sum test for continuous variables and Fisher’s exact test or Pearson’s Chi-squared test for categorical variables. Univariate (UVA) and multivariable analyses (MVA) were performed using Cox regression analysis. Kaplan Meier curves for IBTR and LRR are also provided. All clinical variables which were statistically significant on univariate analysis were included in the MVA. Since shave margin is our main predictor of interest, it was included into the MVA regardless of statistical significance on UVA. Subset UVA, MVA, and analysis of IBTR and LRR using Kaplan Meier curves including only patients with pleomorphic type LCIS were also performed, as it is well recognized as an aggressive variant of LCIS.25 Statistical significance was defined setting alpha at 0.05.
RESULTS
Patient Characteristics
A total of 511 patients who underwent lumpectomy for DCIS or invasive carcinoma associated with NC-LCIS were identified. All patients were female and median age was 60 years [IQR 52–69]; 75% (n=382) were White, 11% (54) were Black, and 15% (n=75) were of other races. The majority of patients had invasive breast cancer (95%, n=486) and 4.9% had DCIS (n=25). The invasive component of disease was lobular histology in 71% (n=364) patients, ductal in 14% (n=74), and mixed ductal and lobular in 14% (n=73). Most had early-stage disease, with 67% having T1 tumors (n=341); 81% (n=413) were pathologically node negative, 95% (n=484) were ER positive, and 90% (n=461) were HER2 negative. Only 3.3% of patients had triple negative disease (n=17). Additional clinical characteristics are shown in Table 1.
TABLE 1.
Patient characteristics of overall cohort by margin status
| Overall Cohort N=511 | Non-Classic LCIS Margin Status | p-value | |||
|---|---|---|---|---|---|
| <2mm N=37 | ≥2mm N=348 | Within shave margin N=126 | |||
| Age at Diagnosis, median (IQR) | 60 (52–69) | 59 (55–66) | 61 (52–70) | 58 (48–67) | 0.026 |
| Race, n (%) | 0.3 | ||||
| Asian/Other | 75 (15%) | 8 (22%) | 51 (15%) | 16 (13%) | |
| Black | 54 (11%) | 6 (16%) | 33 (9.5%) | 15 (12%) | |
| White | 382 (75%) | 23 (62%) | 264 (76%) | 95 (75%) | |
| Invasive Tumor Histology | 0.2 | ||||
| Ductal | 74 (14%) | 5 (14%) | 47 (14%) | 22 (17%) | |
| Lobular | 364 (71%) | 30 (81%) | 253 (73%) | 81 (64%) | |
| Mixed Lobular/Ductal | 73 (14%) | 2 (5.4%) | 48 (14%) | 23 (18%) | |
| T-stage | 0.2 | ||||
| T1 | 341 (67%) | 29 (78%) | 228 (66%) | 84 (67%) | |
| T2/3 | 145 (28%) | 5 (14%) | 102 (29%) | 38 (30%) | |
| TIS | 25 (4.9%) | 3 (8.1%) | 18 (5.2%) | 4 (3.2%) | |
| N-stage | 0.002 | ||||
| N0 | 413 (81%) | 35 (95%) | 289 (83%) | 89 (71%) | |
| N1 | 71 (14%) | 1 (2.7%) | 46 (13%) | 24 (19%) | |
| N2–3 | 27 (5.3%) | 1 (2.7%) | 13 (3.7%) | 13 (10%) | |
| Tumor Grade | 0.045 | ||||
| High | 313 (66%) | 12 (44%) | 220 (67%) | 81 (69%) | |
| Intermediate/Low | 161 (34%) | 15 (56%) | 110 (33%) | 36 (31%) | |
| Unknown | 37 | 10 | 18 | 9 | |
| ER Positive | 484 (95%) | 31 (84%) | 332 (96%) | 121 (96%) | 0.014 |
| PR Positive | 414 (84%)* | 27 (79%) | 288 (86%)* | 99 (80%)* | 0.2 |
| HER2 Positive | 37 (7.4%)* | 6 (17%) | 26 (7.7%)* | 5 (4.0%) | 0.040 |
| Triple Negative Breast Cancer | 17 (3.3%) | 4 (11%) | 10 (2.9%) | 3 (2.4%) | 0.053 |
| Type of NC-LCIS | |||||
| Pleomorphic Type | 147 (29%) | 22 (59%) | 103 (30%) | 22 (17%) | <0.001 |
| Florid/Acinar Expansion | 216 (42%) | 17 (46%) | 150 (43%) | 49 (39%) | 0.6 |
| Necrosis | 133 (26%) | 18 (49%) | 85 (24%) | 30 (24%) | 0.005 |
| Other | 17 (3.3%) | 4 (11%) | 8 (2.3%) | 5 (4.0%) | 0.031 |
| With pleomorphic features | 210 (41%) | 12 (32%) | 134 (39%) | 64 (51%) | 0.030 |
| Radiation Therapy | 439 (86%) | 34 (92%) | 290 (85%)* | 115 (92%)* | 0.081 |
| Chemotherapy | 155 (30%) | 12 (32%) | 100 (29%) | 43 (34%) | 0.5 |
| Any Endocrine Therapy | 438 (86%) | 32 (86%) | 300 (88%)* | 106 (85%)* | 0.7 |
| Compliant with Endocrine therapy | 342 (67%) | 27 (73%) | 233 (67%) | 83 (65%)* | 0.7 |
| Completed 5 years Endocrine therapy | 119 (23%) | 14 (38%) | 62 (18%) | 43 (34%) | <0.001 |
| Length of Follow-Up, years, median (IQR) | 3.37 (1.99–5.85) | 3.77 (2.26–7.17) | 3.00 (1.82–4.98) | 4.82 (2.60–7.40) | <0.001 |
| IBTR | 17 (3.3%) | 0 (0%) | 13 (3.7%) | 4 (3.2%) | 0.8 |
| LRR | 25 (4.9%) | 1 (2.7%) | 17 (4.9%) | 7 (5.6%) | 0.9 |
Unknowns factored into percentage calculations
LCIS lobular carcinoma in situ, IQR interquartile range, ER estrogen receptor, PR progesterone receptor, HER2 human epidermal growth factor receptor 2, NC-LCIS non-classic lobular carcinoma in situ, IBTR ipsilateral breast tumor recurrence, LRR locoregional recurrence
The subtype of NC-LCIS present in all lumpectomy specimens was recorded. The majority of patients had a single type of NC-LCIS (67%, n=341); 33% of patients (n=170) had ≥2 types of NC-LCIS present. The frequency of variants of NC-LCIS was as follows: 42% florid (n=216), 41% pleomorphic features (n=210), 29% pleomorphic type (n=147), and 26% with necrosis (n=133).
Within the entire cohort, 86% (n=439) received radiation therapy and 30% (n=155) received either neoadjuvant or adjuvant chemotherapy. Endocrine therapy was used by 86% (n=438) of the entire cohort, with 67% (n=342) of those taking endocrine therapy being compliant with therapy. The median duration of endocrine therapy was 3.0 years (interquartile range [IQR] 1.6–5.0) with 23% (n=119) having completed at least 5 years at the time of data collection.
Margin Status
All patients underwent lumpectomy with assessment of margin status. Surgical re-excision of margins was performed in 22.3% (n=114) of patients, with 2.3% (n=12) requiring ≥2 re-excisions. Re-excision was performed for DCIS or invasive disease in 89% of cases (n=101), and for NC-LCIS in 11% (n=12). There was no difference in rate of margin re-excision by margin status, with re-excision required in 16% of patients (n=6) with <2mm NC-LCIS margin, 20.6% (n=63) ≥2mm, and 27.4% (n=35) of the within shave margin cohort (p=0.4).
Patient characteristics by margin status are shown in Table 1. Within the study cohort, 68% of patients (n=348) had NC-LCIS margins confirmed to be ≥2mm, and 7.2% (n=37) had margins <2mm, of whom 22% (n=8) had NC-LCIS reported on ink of at least 1 lumpectomy margin (Table 2). An additional 24.6% of patients (n=126) had NC-LCIS within the shave margin, without exact margin distance reported. Of the 163 patients with either <2mm margin or who had NC-LCIS within the shave margin without exact margin distance reported, 113 (69%) had only 1 close NC-LCIS margin, 31 (19%) had 2 close margins, 12 (7.4%) had 3 close margins, 5 (3.1%) had 4 close margins, and 2 (1.2%) had 5 close margins.
TABLE 2.
Patients with NC-LCIS reported on-ink of final lumpectomy margin
| Pt | Age | Invasive Histology | T | N | ER/PR/HER2 | NC-LCIS Type | RT | ET | Duration ET (years) | Follow-Up (years) | IBTR | LRR |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 49 | Lobular | T1 | N0 | +/+/− | Pleomorphic | Yes | No | - | 2.1 | No | No |
| 2 | 52 | Ductal | T1 | N0 | +/+/− | Pleomorphic Large Cell | Yes | Yes | 4.0 | 4.0 | No | No |
| 3 | 52 | Lobular | T1 | N0 | +/+/− | Pleomorphic Necrosis | Yes | Yes | 1.8 | 1.8 | No | No |
| 4 | 57 | Lobular | T1 | N3 | −/−/− | Pleomorphic Signet Ring | Yes | No | - | 2.9 | No | No |
| 5 | 57 | Lobular | T3 | N0 | +/−/− | Pleomorphic Features | Yes | Yes | 1.3 | 1.3 | No | No |
| 6 | 63 | Lobular | T2 | N0 | +/+/− | Pleomorphic | Yes | Yes | 1.1 | 1.1 | No | No |
| 7 | 65 | Ductal | IS | N0 | +/+/− | Florid Pleomorphic Features | Yes | Yes | 1.9 | 2.1 | No | No |
| 8 | 65 | Lobular | T1 | N0 | +/+/− | Pleomorphic Florid Necrosis | Yes | Yes | 2.3 | 2.3 | No | No |
NC-LCIS non-classic lobular carcinoma in situ, ER estrogen receptor, PR progesterone receptor, HER2 human epidermal growth factor receptor 2, RT radiation therapy, ET endocrine therapy, IBTR ipsilateral breast tumor recurrence, LRR locoregional recurrence
Recurrence Outcomes
Median length of follow-up was 3.4 years (IQR 2.0–5.9), with 31.3% (n=160) of patients having ≥5 years of follow-up and 8.0% (n=41) of patients having ≥10 years follow-up. IBTR occurred in 3.3% of patients (n=17) and LRR occurred in 4.9% (n=25) of patients. Recurrences occurred at a median of 2.0 years (IQR 1.6–3.9) after final margins were obtained with either lumpectomy or re-excision.
Rates of IBTR and LRR did not differ significantly by margin status. Those with <2mm margins had a 0% (n=0) rate of IBTR compared to 3.7% (n=13) in those with ≥2mm margins and 3.2% (n=4) in those with NC-LCIS within shave margin (p=0.8). Similarly, rates of LRR did not differ by margin status, with a 2.7% rate (n=1) of LRR in those with <2mm margins, 4.9% (n=17) in those with ≥2mm margins, and 5.6% (n=7) in those with NC-LCIS within shave margin (p=0.9). Kaplan-Meier curves are shown in Figure 1. None of the 8 patients with NC-LCIS reported on ink experienced either an IBTR or an LRR (Table 2).
Fig 1.
Kaplan-Meier curves for (A) IBTR and (B) LRR in entire cohort by NC-LCIS margin status.
IBTR ipsilateral breast tumor recurrence, LRR locoregional recurrence, NC-LCIS non-classic lobular carcinoma in situ
Rate of IBTR and LRR did not differ by number of close NC-LCIS margins. Of the 163 patients with either <2mm margin or who had NC-LCIS within shave margin without exact distance provided, overall rate of IBTR was 2.5% (n=4/163). IBTR occurred in 2.7% of patients with only 1 close margin (n=3/113) and in 2.0% of patients with ≥2 close margins (n=1/50)(p>0.9). Similarly, rate of LRR in those with close margins was 4.9% (n=8/163) and did not differ between those with 1 close margin vs ≥2 close margins (4.4%, n=5/113 vs 6.0%, n=3/50)(p=0.70).
On multivariable analysis, no association between margin status and either IBTR or LRR was identified. The only variable which remained independently associated with IBTR was receipt of radiation therapy (hazard ratio 0.11, 95% confidence interval [CI] 0.03–0.36, p<0.001) even when accounting for margin status (Table 3). LRR was associated with receipt of radiation (hazard ratio 0.15, 95% CI 0.06–0.41, p<0.001), N2/3 disease (hazard ratio 11.3, 95% CI 1.35–94.1, p=0.025) and completion of 5 years of endocrine therapy (hazard ratio 0.23, 95% CI 0.06–0.91, p=0.036)(Table 3).
TABLE 3.
Multivariable analysis for IBTR and LRR
| Hazard Ratio | 95% Confidence Interval | p-value | |
|---|---|---|---|
| Ipsilateral Breast Tumor Recurrence (IBTR) * | |||
| Age at Diagnosis (continuous) | 1.02 | 0.97–1.07 | 0.4 |
| T stage | |||
| T1 | -ref- | -ref- | -ref- |
| T2/3 | 2.38 | 0.85–6.63 | 0.10 |
| TIS | 0.82 | 0.09–7.11 | 0.9 |
| NC-LCIS Margin Status | |||
| <2mm or Within Shave Margin | -ref- | -ref- | -ref- |
| ≥2mm | 1.32 | 0.40–4.34 | 0.6 |
| Received Radiation Therapy | 0.11 | 0.03–0.36 | <0.001 |
| Received Endocrine Therapy | 0.78 | 0.23–2.65 | 0.7 |
| Received 5 Years of Endocrine Therapy | 0.43 | 0.10–1.81 | 0.2 |
| Locoregional Recurrence (LRR) * | |||
| Age at Diagnosis (continuous) | 1.03 | 0.99–1.07 | 0.2 |
| T stage | |||
| T1 | -ref- | -ref- | -ref- |
| T2/3 | 2.09 | 0.85–5.12 | 0.11 |
| TIS | 0.47 | 0.05–4.17 | 0.5 |
| N stage | |||
| N0 | -ref- | -ref- | -ref- |
| N1 | 2.30 | 0.72–7.31 | 0.2 |
| N2/3 | 11.3 | 1.35–94.1 | 0.025 |
| Axillary Surgery | |||
| ALND | -ref- | -ref- | -ref- |
| SLNB | 1.96 | 0.24–16.0 | 0.5 |
| None | 3.44 | 0.42–28.2 | 0.3 |
| NC-LCIS Margin Status | |||
| <2mm or Within Shave Margin | -ref- | -ref- | -ref- |
| ≥2mm | 1.00 | 0.39–2.54 | >0.9 |
| Received Radiation Therapy | 0.15 | 0.06–0.41 | <0.001 |
| Received Endocrine Therapy | 0.84 | 0.29–2.41 | 0.7 |
| Received 5 Years of Endocrine Therapy | 0.23 | 0.06–0.91 | 0.036 |
All variables with p-value <0.05 on univariate analysis included in model plus margin status, although margin status was not significant on univariate analysis (p=0.2 for IBTR, p>0.9 for LRR).
IBTR ipsilateral breast tumor recurrence, LRR locoregional recurrence, NC-LCIS non-classic lobular carcinoma in situ
Subset Analysis of Pleomorphic LCIS
A subset analysis of 147 patients with pleomorphic LCIS was performed. Within this cohort, 21.8% (n=32) required re-excision of margins, which was performed for invasive disease in 81% of cases (n=26), and for pleomorphic LCIS in 19% of cases (n=6). Final margin for pleomorphic LCIS was <2mm in 15% of cases (n=22), ≥2mm in 70% (n=103), and within shave margin in 15% (n=22). Adjuvant endocrine therapy was given to 84% (n=123), with 72% (n=88) of those taking endocrine therapy being compliant with therapy. Radiation therapy was given to 84% (n=123) of patients, and 35% (n=52) received either neoadjuvant or adjuvant chemotherapy.
Neither rate of IBTR nor LRR differed by margin status on subset analysis of those with pleomorphic LCIS. Rate of IBTR was 0% (n=0) for those with <2mm margins, 4.9% (n=5) for those with ≥2mm margins, and 4.5% (n=1) for those within shave margin (p=0.8). Similarly, rate of LRR was 4.5% (n=1) for those with <2mm margins, 5.8% (n=6) for those with ≥2mm margins, and 9.1% (n=2) for those with pleomorphic LCIS within shave margin (p=0.9). Kaplan-Meier curves are shown in Figure 2.
Fig. 2.
Kaplan-Meier curves for (A) IBTR and (B) LRR in only patients with Pleomorphic LCIS by NC-LCIS margin status.
IBTR ipsilateral breast tumor recurrence, LRR locoregional recurrence, LCIS lobular carcinoma in situ, NC-LCIS non-classic lobular carcinoma in situ
DISCUSSION
Currently, no guidelines exist for appropriate margin width of NC-LCIS in the setting of concurrent ipsilateral DCIS or invasive breast cancer. The present study identified no association between margin status of NC-LCIS and either IBTR or LRR in patients who had concurrent, ipsilateral breast cancer. Rather, adjuvant therapies, including radiation and endocrine therapy, had the greatest influence on local recurrence. The present study is, to our knowledge, the largest among existing studies examining associations between recurrence and margin involvement by NC-LCIS in the setting of concurrent, ipsilateral breast cancer.
Consensus guidelines for appropriate cancer margin status after a lumpectomy have been established based upon risk of IBTR. The SSO-ASTRO Consensus Guidelines recommend no tumor on ink for invasive cancer, with or without DCIS, and ≥2mm for DCIS, with or without microinvasion, as both cutoffs were shown on meta-analyses to minimize risk of IBTR.27, 28 Prior studies have demonstrated absence of influence with classic LCIS on local recurrence.21 Ciocca et al. demonstrated in a retrospective analysis of 2894 patients undergoing breast-conserving therapy for either DCIS or invasive breast cancer that the 10-year actuarial rate of local recurrence was 15% in patients with margins free of LCIS, and 6% in those with LCIS at the margin (p=NS).21 Based on these data, it is standard of care to not recommend re-excision for a positive classic LCIS margin alone.
Studies examining the biology of NC-LCIS compared to classic LCIS support the hesitancy of many to apply data regarding margin status of classic LCIS to NC-LCIS. Others have shown that NC-LCIS, specifically pleomorphic and florid LCIS, are more likely to have higher Ki-67 index and HER2 expression compared to classic LCIS.22 These data combined with high rates of upgrade to invasive cancer with NC-LCIS12,14 suggest that the biologic implications, and therefore clinical importance, of pleomorphic LCIS differs from that of classic LCIS. While these data support the need to analyze margin status for NC-LCIS separate from classic LCIS, they do not demonstrate by themselves that a specific margin distance of NC-LCIS is warranted.
Prior recommendations that negative margins for NC-LCIS were necessary were based upon the results of small retrospective analyses.10,23,24 Downs-Kelly et al. published their experience with pleomorphic LCIS at the margin of a lumpectomy specimen.24 Their cohort consisted of 26 patients, of whom 20 had pleomorphic LCIS alone and 6 had pleomorphic LCIS in the setting of an ipsilateral invasive breast cancer. Six of 26 patients had pleomorphic LCIS at the specimen margin. With a mean follow-up of 46 months (range 4–108), 1 patient developed recurrent pleomorphic LCIS and this patient did have pleomorphic LCIS at the initial specimen margin. There were no invasive recurrences. This study concluded that obtaining local control with methods including excision to margins of 2mm may be appropriate; however, it acknowledged its limitations given its small cohort size. In 2022 Brock reviewed 6 retrospective studies of NC-LCIS variants, which included a total of 96 patients, and concluded that in patients who had a recurrence of either invasive carcinoma or pleomorphic LCIS, a higher proportion had positive pleomorphic LCIS margins (38%) compared to those who did not have a recurrence (23%).23 Given the small cohort size of these studies, expert consensus guidelines do not provide recommendations for margin width for NC-LCIS, explicitly stating that the available data were not sufficient to provide firm recommendations.18,25 Our study, however, includes a substantially larger population than all prior studies when combined. Additionally, our cohort is less heterogeneous in its surgical management, definition of margin status, and inclusion of only DCIS or invasive recurrences as a primary outcome, which may allow stronger conclusions to be drawn.
There have been other small studies examining pure NC-LCIS, without an associated cancer, with similar findings to our study showing a lack of association between NC-LCIS margin status and local recurrence.26 Khoury et al. performed a multi-institutional retrospective analysis of 47 patients with pleomorphic LCIS, of whom 31 had pure pleomorphic LCIS, 3 had concurrent breast cancer, and 13 had prior history of breast cancer. A subset analysis was performed on those 31 patients with pure pleomorphic LCIS to examine factors associated with local recurrence. When comparing the 6 patients who developed a local recurrence to the 25 who did not, similar to the findings in the present study, there was no difference in proportion of patients who had a positive pleomorphic LCIS margin (2/6 vs 7/25, p=NS).26 Khoury concluded that although there is a high rate of local recurrence after excision of pure pleomorphic LCIS, they were unable to draw a conclusion at that time on adequate margin status given the small cohort size.
Limitations of our study include those biases related to any single-institution study performed with a homogenous population as well as the limitations in granularity of data and selection bias associated with retrospective analyses. Additionally, there are only 8 patients in the present cohort with a true positive margin, which may limit the ability to discern an association between margin status and recurrence; however, to our knowledge, this is the largest cohort overall of patients with NC-LCIS and margin status. Follow-up was a median of 3.4 years, and in a cohort of majority ER positive tumors, there are likely to be late local recurrences which are not captured and for which longer-term follow-up is necessary. Lastly, 25% of patients with NC-LCIS did not have a precise margin distance provided, which is likely due to the study cohort including patients diagnosed prior to the World Health Organization updating recommendations to report pleomorphic LCIS margins in 2019.8,9 We therefore have a subset of patients in whom the exact margin status is not known.
Conclusions
For completely excised invasive breast cancers associated with NC-LCIS, extent of margin width for NC-LCIS was not associated with a difference in IBTR or LRR. Rather, adjuvant therapies directed toward reducing recurrence risk from the invasive cancer, including radiation therapy and endocrine therapy, were independently associated with risk of local recurrence. These data suggest that the decision to perform margin re-excision after lumpectomy should be driven by the invasive cancer, rather than the NC-LCIS margin.
Synopsis.
: Margin width for non-classic LCIS in the setting of DCIS or invasive breast cancer was examined. Margins <2mm had similar rates of recurrence as ≥2mm, suggesting the decision to re-excise margins should not be driven by the NC-LCIS margin.
ACKNOWLEDGEMENTS
The preparation of this study was supported in part by NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center, and this study was presented in oral format at the 24th Annual Meeting of the American Society of Breast Surgeons, April 26–30, 2023, Boston, MA. All authors have no conflicts of interest to disclose.
Footnotes
Disclosures: The preparation of this study was supported in part by NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center, and this study was presented in oral format at the 24th Annual Meeting of the American Society of Breast Surgeons, April 26–30, 2023, Boston, MA. All authors have no conflicts of interest to disclose.
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