Outcomes of classic lobular neoplasia diagnosed on breast core needle biopsy: a retrospective multi-center study.

Both atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) have traditionally been considered to be risk factors for the development of invasive carcinoma and are followed by close observation. Recent studies have suggested that these lesions may represent true precursors with progression to invasive carcinoma. Due to the debate over the significance of these lesions and the small number of cases reported in the literature, the treatment for lobular neoplasia diagnosed by percutaneous core biopsy (PCB) remains controversial. To review our experience with pure LCIS or ALH diagnosed by PCB and correlate the radiologic findings and surgical excision diagnoses to develop management guidelines for lobular neoplasia diagnosed by PCB. We searched the pathology database for patients who underwent PCB with a diagnosis of either pure LCIS or ALH and had subsequent surgical excision. We compared the core diagnoses with the surgical excision diagnoses and the radiologic findings. Thirty-eight PCBs with a diagnosis of ALH (18 cases) or LCIS (20 cases) were identified. Carcinoma was present at excision in 1 (6%) of the ALH cases and in 2 (10%) of the LCIS cases. In summary, 8% (3/38) of PCBs diagnosed as lobular neoplasia (ALH or LCIS) were upgraded to carcinoma (invasive carcinoma or ductal carcinoma in situ) at excision. Surgical excision is indicated for all PCBs diagnosed as ALH or LCIS, as a significant percentage will show carcinoma at excision.

Mixed invasive ductal and lobular carcinoma (Mixed IDC/L) is a rare subtype (3-5%) of invasive breast cancer with elusive pathophysiology. This entity is characterized by a mixed population of both ductal and lobular components within an individual tumor. Few studies have been published to date which compare Mixed IDC/L to invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) from a histopathologic perspective. Available literature on this topic is sparse and has been conflicting with regards to outcomes, and no studies to date describe the response of Mixed IDC/L to neoadjuvant chemotherapy. Patients with ILC have been shown to have lower response rates to neoadjuvant chemotherapy as compared to patients with IDC, which in turn leads to lower rates of successful breast conserving surgery and higher rates of re-excision due to positive margins. We aimed to compare Mixed IDC/L to pure ILC with regards to response to neoadjuvant chemotherapy and the need for repeat surgical intervention. We identified 26 patients with Mixed IDC/L and 113 patients with ILC who received neoadjuvant chemotherapy at our institution between 1990 – 2017. At baseline, the groups had a similar median age, as well as ER H-score, PR H-score, and Ki-67 index. There was no statistical difference in rates of pathologic complete response (pCR) or percent tumor volume reduction post therapy between the two groups. Similarly, the percent of patients that required re-excision was not statistically different. Interestingly, the metastatic pattern was similar between the groups and included sites of dissemination such as the peritoneal cavity and omentum, which are not common sites of metastasis for IDC. These findings suggest that Mixed IDC/L tumors behave similarly to ILC with regard to their response to neoadjuvant chemotherapy and patterns of metastatic spread. These findings support a prominent role for the lobular component in this mixed subtype in driving biology, including response to neoadjuvant therapy and metastatic dissemination. Ongoing efforts are directed towards incorporating data from the IDC cohort, as well as evaluation of changes in histology, ER/PR H-scores, and Ki-67 levels as a result of therapy. These data may imply that Mixed IDC/L tumors may behave clinically more like ILC than IDC, but larger studies are needed to study this rare breast cancer subtype. Citation Format: Azadeh Nasrazadani, Jennifer M Atkinson, Yujia Li, Priscilla F McAuliffe, Rachel C Jankowitz, Leisha A Emens, George C Tseng, Adrian V Lee, Norman Wolmark, Steffi Oesterreich, Peter C Lucas. Mixed invasive ductal and lobular carcinoma (IDC/L) behaves similarly to invasive lobular carcinoma (ILC) with regard to neoadjuvant chemotherapy response and metastatic dissemination [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-26.

The management of lobular neoplasia (LN) on percutaneous core breast biopsies remains controversial. Published upgrade rates after surgical excision vary widely. This study aims to determine the frequency of malignancy following excision in patients with LN found on core biopsy. Our study identified patients from December 2005 through December 2010 with LN as the highest-risk lesion on core biopsy. Patients with flat epithelial atypia on core biopsy were not excluded. Per institutional policy, excision was routinely recommended. An upgrade from the core biopsy of LN was defined as excisional biopsy pathology that revealed ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), or invasive lobular carcinoma (ILC). Between December 2005 and December 2010, 4472 percutaneous breast biopsies were performed, with 71 patients (1.5%) having LN as the highest-risk lesion on core biopsy. Sixty-seven patients (94%) underwent excision. The upgrade rate on excisional biopsy was 16% (11/67 patients), with the type of malignancy on excisional biopsy pathology as follows: DCIS, 36% (4/11); IDC, 18% (2/11); and ILC, 45% (5/11). All patients with pleomorphic lobular carcinoma in situ on core biopsy who proceeded to excision were upgraded to malignancy. After excluding patients with discordant results, patients with pleomorphic lobular carcinoma in situ, and patients with flat epithelial atypia on core biopsy, the upgrade rate of pure LN on excisional biopsy was 9%. LN on core biopsy warrants excisional biopsy given the upgrade rate to malignancy.

In 1973, the European Institute of Oncology performed the first prospective neoadjuvant chemotherapy study in locally advanced, inoperable breast cancer. The original purpose was to downstage the primary tumor in order to achieve surgical resection. This approach has subsequently increased in popularity, and in the last 10 years, randomized controlled trials of neoadjuvant chemotherapy have been performed with a view to further downstage the primary tumor and lymph nodes in order to achieve greater rates of breast-conserving surgery and to test whether systemic therapy given earlier would confer a survival benefit. Although the net result of these trials did demonstrate a higher rate of breast conservation, no overall survival benefit was seen. However, in subgroup analysis, there was a significant survival benefit in patients in whom a complete pathologic response (pCR) was achieved. In the National Surgical Adjuvant Breast and Bowel Project B-18 trial of neoadjuvant chemotherapy, at 9 years median follow-up, the overall survival rate for patients achieving a pCR was 85% compared with 73% in those in whom residual cancer was detected on histopathologic examination. For disease-free survival, the respective rates were 75% and 58%. After adjustment for other prognostic factors, achievement of a pCR was associated with a 50% reduction in deaths compared with the group as a whole. Mauri et al evaluated nine randomized studies, with a total of 3,946 patients with breast cancer in whom neoadjuvant therapy was compared with adjuvant systemic therapy. They found no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms with regard to overall survival, disease progression, or distant disease recurrence. However, they observed that neoadjuvant therapy was associated with an increased risk of locoregional disease recurrence compared with adjuvant therapy, especially in trials where more patients in the neoadjuvant arm received radiation therapy without surgery. In several retrospective studies, the pCR rates in invasive ductal breast carcinoma (no special type) have been shown to be approximately 15% or less, whereas the pCR rates in invasive lobular carcinoma have been shown to be 2% or less. Katz et al reviewed randomized trials of neoadjuvant chemotherapy and noted that the pCR rate was 1.7% in invasive lobular carcinoma and 11.6% in invasive ductal breast carcinoma (no special type). Regarding invasive lobular carcinoma, they concluded: “the benefit from systemic chemotherapy for individuals with this form of breast disease is unclear.” Similarly, two retrospective studies have demonstrated low rates of successful breast conservation for patients with lobular carcinoma who underwent neoadjuvant chemotherapy. In patients who received breast-conserving surgery after neoadjuvant therapy, Soucy et al found surgical margin involvement in 43% of patients with lobular carcinoma compared with 16% of patients with invasive ductal carcinoma (no special type). Another study, from the M. D. Anderson Cancer Center, of 284 consecutive patients diagnosed with pure invasive lobular carcinoma between 1998 and 2006 compared patients who received neoadjuvant chemotherapy with those who received primary surgery as first-line treatment and concluded that neoadjuvant chemotherapy did not increase the rates of breast conservation in this morphologic subtype. It should be noted that the above studies are retrospective, not randomized, trials. In the three randomized trials of neoadjuvant endocrine therapy (P024 conducted by the Letrozole Neoadjuvant Breast Cancer Study Group, IMPACT [Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen], and PROACT [Pre-Operative “Arimidex” Compared to Tamoxifen]) for women with estrogen receptor (ER) –positive disease, none of which carried out analysis of histological tumor type (ie, lobular v ductal [no special type]), a higher rate of breast conservation was observed in women who received preoperative endocrine treatment. The lack of subgroup analysis in these three studies does not allow one to draw conclusions regarding histologic type-specific effectiveness of neoadjuvant endocrine treatment, although classical lobular carcinoma is well recognized as more often being ER positive than ductal tumors (no special type). JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 28 NUMBER 22 AUGUST 1 2010

AimsThe clinical significance of radial scar (RS)/complex sclerosing lesion (CSL) with high-risk lesions (epithelial atypia) diagnosed on needle core biopsy is not well defined. We aimed at assessing the upgrade...

To evaluate the relative effectiveness of letrozole compared with tamoxifen for patients with invasive ductal or lobular carcinoma. Patients diagnosed with early-stage invasive ductal carcinoma (IDC) or classic invasive lobular carcinoma (ILC) who were randomly assigned onto the Breast International Group (BIG) 1-98 trial and who had centrally reviewed pathology data were included (N = 2,923). HER2-negative IDC and ILC were additionally classified as hormone receptor-positive with high (luminal B [LB] -like) or low (luminal A [LA] -like) proliferative activity by Ki-67 labeling index. Survival analyses were performed with weighted Cox models that used inverse probability of censoring weighted modeling. The median follow-up time was 8.1 years. In multivariable models for disease-free survival (DFS), significant interactions between treatment and histology (ILC or IDC; P = .006) and treatment and subgroup (LB like or LA like; P = .01) were observed. In the ILC subset, there was a 66% reduction in the hazard of a DFS event with letrozole for LB (hazard ratio [HR], 0.34; 95% CI, 0.21 to 0.55) and a 50% reduction for LA subtypes (HR, 0.50; 95% CI, 0.32 to 0.78). In the IDC subset, there was a significant 35% reduction in the hazard of a DFS event with letrozole for the LB subtype (HR, 0.65; 95% CI, 0.53 to 0.79), but no difference between treatments was noted for IDC and the LA subtype (HR, 0.95; 95% CI, 0.76 to 1.20). The magnitude of benefit of adjuvant letrozole is greater for patients diagnosed with lobular carcinoma versus ductal carcinoma.

Background: Breast conserving surgery (BCS) and its following radiotherapy is an accepted therapeutic method for patients with invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). Objectives: The aim of this study was to investigate the effect of intraoperative electron radiotherapy on women with breast cancer (invasive lobular and ductal carcinoma). Methods: Between August 2013 and September 2017, 968 patients, who were referred to Cancer Research Center, Shahid Beheshti University of Medical Sciences with invasive breast cancer, were treated with breast-conserving surgery and radiotherapy. Of those, 426 patients received a tumor bed boost with intraoperative electron radiotherapy (IOERT) during lumpectomy (58 patients with pure invasive lobular carcinoma, 239 patients with pure invasive ductal carcinoma, and 129 patients with other diagnoses). 542 patients received a tumor bed boost with conventional external beam radiotherapy post lumpectomy (24 patients with pure invasive lobular carcinoma, 418 patients with pure invasive ductal carcinoma, and 100 patients with other diagnoses). The patients were followed up to 49 months. A comprehensive list of clinical and pathologic features was evaluated for all patients. We retrospectively analyzed outcomes of breast cancer treated with boost intraoperative electron radiotherapy (pure ILC and IDC groups) and in other group treated with boost conventional external beam radiotherapy (pure ILC group). Results: None of the ILC patients had recurrence in the two groups. The four-year survival rate for ILC patients was 100%, but in the IDC group the survival rate was 97%. Survival analyses showed patients with IDC had a higher risk of ipsilateral breast tumor recurrence (IBTR) and metastasis. Conclusions: Overall, the rates of IBTR and metastasis in the ILC boost IOERT group were significantly low. This finding suggests that IOERT technique deployment in ILC had no inferiority compared with the control group.

Introduction/Objective Mucocele-like lesions (MLLs) are characterized by cystically dilated, mucin-filled ducts, usually associated with rupture and extravasation of mucin into the stroma. The epithelium lining the ducts may be attenuated or show a spectrum of proliferative changes ranging from hyperplasia to atypical hyperplasia to ductal carcinoma in situ (DCIS). Our study aims to evaluate the necessity of excision of pure MLL without atypia diagnosed on core needle biopsy (CNB). Methods/Case Report We retrospectively identified all subsequent in-house CNBs obtained between January 2017- August 2022 with MLLs. We reviewed all CNB slides with the diagnosis containing a “mucocele-like lesion” and assessed radiologic-pathologic concordance. An upgrade was defined as invasive carcinoma and/or DCIS in the excision. The excision slides of all upgraded cases were re-reviewed. Out of ~16000 consecutive CNBs in the study period, 69 CNBs from 69 patients yielded MLL alone, MLL with atypia, or MLL with carcinoma. We excluded 43 CNBs (7 patients with prior/concurrent carcinoma and 36 without excision). The final cohort consisted of 25 CNBs (14 with pure mucocele-like lesions and 11 MLLs with atypia). The CNB targeted mammographic calcifications in 42 cases, and 4 sonographic mass. Results (if a Case Study enter NA) Subsequent excision or clinical follow-up was available for 14 pure MLLs—of which one was upgraded. Five excisions showed atypia (4 atypical ductal hyperplasias (ADH) and one atypical lobular hyperplasia (ALH)). Excisions of 11 MLL with atypia yielded 1 case upgraded to DCIS (9.09%, 1/11) and seven excisions showed atypia (5 ADH, 1 ALH, and 1 flat epithelial atypia). DCIS in an upgraded case was in an area with biopsy site changes. There was no upgrade to invasive carcinoma in either group. Among the 36 MLLs excluded from the study due to not having excision available for review, twelve were followed up with interval radiology and showed either stable lesions or no residual calcifications. Conclusion There was one case with upgrade of pure MLLs in our series. Clinicoradiological surveillance can be considered in a patient without prior/current carcinoma in pathological-radiological concordant CNB diagnosis of pure MLL.

Flat epithelial atypia (FEA) of the breast have a tendency to calcify and, as such, are becoming increasingly detected by mammography. There is no consensus yet on whether to excise these lesions or not after diagnosis on core needle biopsies (CNB). We reviewed 3,948 cases of breast CNB between June 2004 and June 2009 correlating histomorphologic, radiological, and clinical features. There were 3.7 % (145/3,948) pure FEA and 1.5 % (58/3,948) concomitant FEA and atypical ductal hyperplasia (ADH). In the pure FEA population, 46.2 % (67/145) had microcalcifications on mammography with 65.5 % (95/145) of patients undergoing subsequent excisional biopsies with the following findings: benign 20 % (19/95), ADH 37.9 % (36/95), ductal carcinoma in situ (DCIS) 1.1 % (1/95), and DCIS and invasive ductal carcinoma (IDC) 2.1 % (2/95). In the concomitant FEA and ADH group, 86.2 % (50/58) patients had microcalcifications on radiograph with 74.1 % (43/58) of patients undergoing subsequent excisions with: benign 23.3 % (10/43), DCIS 9.3 % (4/43), DCIS and IDC 4.7 % (2/43), DCIS + lobular carcinoma in situ + invasive lobular carcinoma 2.3 % (1/43), and tubular carcinoma 2.3 % (1/43). The incidence of carcinoma in the FEA + ADH group is 18.6 % (8/43) and 3.2 % (3/95) for the pure FEA group. This difference is statistically significant (p = 0.0016). The relative risk of carcinoma in the ADH + FEA group versus the pure FEA group is 6.4773, with 95 % CI of 1.8432 and 22.76 24. Five-year mean follow-up in the unexcised pure FEA did not show any malignancies. These findings suggest that pure FEA has a very low association with carcinoma, and these patients may benefit from close clinical and mammographic follow-up while the combined pure FEA and ADH cases may be re-excised.

Invasive lobular carcinoma (ILC) and lobular neoplasia (LN) are two distinct conditions that still pose challenges regarding to their classification, diagnosis and management. Although they share similar cellular characteristics, such as discohesive neoplastic cells and absence of e-cadherin staining, they represent completely different conditions. LN encompasses atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), which are currently considered risk factors and non-obligatory precursors of breast neoplasia. These lesions are diagnosed as incidental findings in percutaneous biopsies or appear as non-specific clusters of punctate calcifications in mammograms. ILC is the second most common breast malignancy and has typical histological features, such as infiltrative growth and low desmoplasia. These histological features are reflected in imaging findings and constitute the reasons for typical subtle mammographic features of ILC, as architectural distortion or focal asymmetries. Ultrasonography (US) may detect almost 75 % of the ILCs missed by mammography and represents the modality of choice for guiding biopsies. Magnetic resonance imaging (MRI) exhibits a high sensitivity for the diagnosis of ILC and for detecting synchronous lesions. Teaching Points • LN includes ALH and LCIS, risk factors and non-obligatory precursors of breast cancer.• Absence of e-cadherin staining is crucial for differentiation among ductal and lobular lesions.• ILC has typical histological features, such as infiltrative growth and low desmoplasia.• Mammographic features of ILC are often subtle and reflect the histological features.• MRI exhibits a high sensitivity for the diagnosis of ILC and for detecting synchronous lesions.

Caveolin-1 expression in human breast lobular cancer progression

Based on modern series demonstrating low upgrade rates for pure lobular neoplasia (LN) diagnosed on core needle biopsy (CNB), our institution no longer recommends routine excision, provided imaging is concordant. This study describes outcomes in patients managed without surgical excision. From an institutional database, we identified all patients with a diagnosis of pure atypical lobular hyperplasia and/or classic lobular carcinoma in situ on CNB managed without surgical excision (i.e., conservative management) from 2015 to 2019. The primary outcome of interest was failure of conservative management, defined as development of ipsilateral same-quadrant ductal carcinoma in situ or invasive breast cancer within 2 years of CNB, or need for ipsilateral same-quadrant excisional biopsy. We also evaluated rates of ipsilateral same-quadrant CNB during follow-up. Among 96 pure LN lesions on CNB since 2015, 80 (83%) were managed without surgical excision. Median follow-up was 27 months (IQR: 16-28), with only 2 (2%) patients lost to follow-up. No patients developed an ipsilateral, same-quadrant breast cancer. The 3-year risk of conservative management failure was 6.2% (95% CI 2.3-15.7%). All failures were a result of need for excisional biopsy due to progressive imaging abnormalities at the initial CNB site, with benign final pathology. The 3-year risk of ipsilateral same-quadrant CNB was 9.2% (95% CI 3.8-21.5%). Non-surgical management of pure LN is safe, and the likelihood of requiring subsequent surgical excision or repeat CNB during follow-up is low. These data provide reassurance that routine excision of pure LN in the setting of radiologic-pathologic concordance is not required.

Recent reports suggest that the finding of lobular neoplasia (atypical lobular hyperplasia [ALH] or bular carcinoma in situ [LCIS]) in breast core needle biopsy specimens may be associated with an increased risk of both ductal carcinoma in situ (DCIS) or invasive carcinoma at excision. We reviewed our breast core biopsy material to see if we could confirm this finding. from 4,297 biopsies, 71 cases of lobular neoplasia lone and 35 cases of lobular neoplasia associated with typical ductal hyperplasia were identified. Biopsy follow-up revealed DCIS or invasive carcinoma in none of 6 cases of ALH, none of 9 cases of LCIS, and DCIS in 1 of 11 cases with both atypical ductal hyperplasia and LCIS. Our results suggest that patients with lobular eoplasia in breast core biopsy specimens are not at increased risk of either DCIS or invasive carcinoma at excision, and patients with this finding and no other linical or pathologic indications for biopsy can be llowed up rather than routinely undergo excision.

This study correlates ductal intraepithelial neoplasia (DIN) 1A diagnosed at stereotactic spring core needle biopsy (CNB) or vacuum-assisted biopsy (VAB) with the subsequent surgical histologic results or long-term follow-up imaging findings to predict the likelihood of upgrade to ductal carcinoma in situ (DCIS) or invasive carcinoma. Stereotactic imaging-guided CNBs and VABs were performed principally for assessment of microcalcifications seen on mammography. DIN 1A diagnoses made at CNB or VAB were correlated with subsequent excisional biopsy results or imaging follow-up. Patients were included only if there was no concomitant CNB or VAB diagnosis of DIN 1B, atypical lobular hyperplasia, lobular carcinoma in situ or DCIS, papillary lesion, or invasive carcinoma. Surgical biopsy results were obtained for 239 patients. Upgrade was defined as a diagnosis of DCIS or invasive carcinoma at surgery. Patients who did not undergo surgical excision were followed with imaging. An upgrade rate of 4.2% (10 lesions in 239 patients) is reported. The remaining samples (229/239) had a surgical diagnosis of DIN 1A or DIN 1B, lobular carcinoma in situ, or a benign finding with no atypia. The upgrade rate of DIN 1A diagnosed at CNB or VAB was 4.2%. These results indicate it may be reasonable to avert immediate surgery in favor of short-term imaging follow-up.

Background: Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer after invasive ductal carcinoma (IDC). While specific clinical and pathological features differ between ILC and IDC, both histologies are treated the same, due to a lack of knowledge of targetable pathways underlying the observed differences. To identify potential genetic drivers of ILC progression, we set out to identify genes with copy number (CN) alterations, comparing tumors with good outcome to those with poor outcome. Method: We designed probes for a total of 67 genes known to be frequently altered in breast cancer and used sensitive nanoString technology to comprehensively investigate CN alterations of these genes in 70 well-curated primary ILCs. ILC cell lines MDA-MB-134-VI, SUM44PE, and BCK4 were used for functional studies including proliferation, apoptosis, colony formation, and analysis of gene expression. Results: Our studies reveal that ESR1 is frequently amplified in primary ILC (14% gains and 10% amplification), and that tumors with amplified ESR1 are more likely to recur compared to those with normal CN. Our analysis also identified a subset of ILCs with HER2 amplification (19%) despite a negative clinical IHC score, and these tumors expressed high HER2 mRNA, protein, and demonstrated enrichment of a molecular HER2 signature. The other most frequently amplified genes included CCND1 (33%), MDM4 (17%), and MYC (17%), and most frequently lost genes were NCOR2 (7%), FGFR4 (6%) and TP53 (6%). MDM4, a negative regulator of p53, has previously been reported to play a role in breast cancer, though little is known about its role in ILC. We demonstrate that decreasing MDM4 levels in p53 wild type ILC cell lines results in increased apoptosis, decreased proliferation associated with cell cycle arrest, and activation of p53 target genes. Intriguingly, a similar induction of G0/G1 cell cycle arrest and increase in apoptosis was observed in p53 mutant ILC cells after MDM4 downregulation, suggesting a p53-independent function of MDM4. Conclusion: Sensitive detection of CN changes identified amplifications of ESR1 and MDM4 as potential drivers of ILC. Functional studies demonstrate that MDM4 has both p53 dependent and independent functions that warrant further study. Citation Format: Atkinson JM, Cao L, Basudan A, Sikora MJ, Bahreini A, Tasdemir N, Jankowitz RC, McAuliffe PF, Dabbs D, Haupt S, Haupt Y, Peter Lucas PC, Lee AV, Oesterreich S. Copy number analysis identifies ESR1 and MDM4 as drivers of progression in invasive lobular breast carcinoma [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-03.