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Case #84: classic lobular carcinoma in situ and associated low-grade ductal carcinoma in situ. (A) Terminal duct lobular units expanded by classic lobular carcinoma in situ (LCIS; H & E, 200×). (B) Lack of membranous E-cadherin immunoreactivity on LCIS cells. The residual luminal cells show strong membrane staining (E-cadherin, 100×). (C) Low-grade ductal carcinoma in situ (DCIS) showing a prominent cribriform pattern (H & E, 100×). (D) Strong, uniform membrane staining with E-cadherin on DCIS cells (E-cadherin, 100×).
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Introduction
Lobular carcinoma in situ (LCIS) has been accepted as a marker of risk for the development of invasive breast cancer, yet modern models of breast carcinogenesis include LCIS as a precursor of low-grade carcinomas. We provide evidence favoring a clonal origin for LCIS and synchronous estrogen receptor-positive malignant lesions of the d...
Citations
... Lobular carcinoma in situ (LCIS), originally described in 1941, is now recognized as both a risk factor and a non-obligate precursor for subsequent breast cancer [1][2][3][4]. LCIS is a form of lobular neoplasia characterized by the proliferation of loosely cohesive, neoplastic cells that fill and distend most (> 50%) acini of the terminal duct lobular units where they are centered [3,5]. A 2% annual incidence of breast cancer among women with classic-type LCIS has been reported, conferring up to a tenfold increased breast cancer risk compared with the general population [6]. ...
... LCIS is an established breast cancer risk factor, associated with a 2% annual incidence of breast cancer development and up to a tenfold increased breast cancer risk compared with the general population [2][3][4]6]. Prior work has shown that women with LCIS who are diagnosed with a subsequent breast cancer are often diagnosed at an early stage with hormone receptor-positive tumors and have excellent breast cancer-specific survival (98.9% and 96.3% at 10 and 20 years, respectively), but data regarding the risk of subsequent CBC development in this population are lacking [27]. ...
Purpose
Lobular carcinoma in situ (LCIS) confers increased cancer risk in either breast, but it remains unclear if this population is at increased risk for bilateral breast cancer (BC) development. Here we report bilateral BC incidence among women with a history of LCIS.
Methods
Women with classic-type LCIS diagnosed from 1980 to 2017 who developed unilateral BC (UBC) or bilateral BC were identified. Bilateral BC was categorized as synchronous (bilateral BC diagnosed < 6 months apart; SBBC) or metachronous (bilateral BC diagnosed ≥ 6 months apart; MBBC). Five-year incidence rates of bilateral BC among this population were evaluated. Comparisons were made to identify factors associated with bilateral BC.
Results
At 7 years’ median follow-up, 249/1651 (15%) women with LCIS developed BC; 34 with bilateral BC (2%). There were no clinicopathologic feature differences between those with UBC and bilateral BC. SBBC occurred in 18 without significant differences versus UBC. Among 211 with UBC and a contralateral breast at risk, 16 developed MBBC at a median follow-up of 3 years. MBBC patients were less likely to receive endocrine therapy and more likely to receive chemotherapy versus UBC. Tumor histology was not associated with MBBC. Estimated 5-year MBBC risk was 6.4%. Index estrogen/progesterone receptor positivity and endocrine therapy were the only factors associated with MBBC risk.
Conclusion
Bilateral BC occurred in 2% of women with LCIS history at median follow-up of 7 years. Similar to the general BC population, a decrease in MBBC is seen among women with a history of LCIS who develop hormone receptor-positive disease and those who receive endocrine therapy, highlighting the protective effects of this treatment.
... In many cases, careful observation may be recommended to monitor signs of invasive BC progression. This includes breast self-exams, clinical breast exams, mammogram, and MRI (22). Due to the low incidence rate and lack of clear identification by breast imaging, the management of LCIS is a controversial issue (23). ...
Breast cancer (BC) prevention remains the ultimate cost-effective method to reduce the global burden of invasive breast cancer (IBC). To date, surgery and chemoprevention remain the main risk-reducing modalities for those with hereditary cancer syndromes, as well as high-risk non-hereditary breast lesions such as ADH, ALH, or LCIS. Ductal carcinoma in situ (DCIS) is a preinvasive malignant lesion of the breast that closely mirrors IBC and, if left untreated, develops into IBC in up to 50% of lesions. Certain high-risk patients with DCIS may have a 25% risk of developing recurrent DCIS or IBC, even after surgical resection. The development of breast cancer elicits a strong immune response, which brings to prominence the numerous advantages associated with immune-based cancer prevention over drug-based chemoprevention, supported by the success of dendritic cell vaccines targeting HER2-expressing BC. Vaccination against BC to prevent or interrupt the process of BC development remains elusive but is a viable option. Vaccination to intercept preinvasive or premalignant breast conditions may be possible by interrupting the expression pattern of various oncodrivers. Growth factors may also function as potential immune targets to prevent breast cancer progression. Furthermore, neoantigens also serve as effective targets for interception by virtue of strong immunogenicity. It is noteworthy that the immune response also needs to be strong enough to result in target lesion elimination to avoid immunoediting as it may occur in IBC arising from DCIS. Overall, if the issue of vaccine targets can be solved by interrupting premalignant lesions, there is a potential to prevent the development of IBC.
... 2 In clinical practice, patients with DCIS can also have concomitant lobular carcinoma in situ (LCIS), which was considered a risk factor for breast cancer. [13][14][15] However, the incidence of LCIS is much lower than DCIS with approximately 2.75 cases per 100,000 women(representing 1-2% of all breast cancers). 16,17 Similar to DCIS, the long-term prognosis of LCIS is very good with a 10-and 20-year cancer-specific overall survival rate of 98.9% and 96.3%, respectively. ...
Purpose
Although breast conservation surgery(BCS) followed by adjuvant radiotherapy is now the mainstream treatment method for breast ductal carcinoma in situ(DCIS), mastectomy is still performed in some patients who refuse to undergo radiation. However, the most effective treatment method for these patients is still unknown. In the current study, we aimed to compare the survival rates between mastectomy and BCS plus adjuvant radiotherapy in patients with DCIS.
Materials and Methods
We performed a retrospective study of 333 patients with DCIS from May 2004 to December 2016. There were 209 patents who were treated with BCS and adjuvant radiotherapy, while the remaining of 124 patients underwent mastectomy. The disease-free survival (DFS) and local recurrence-free survival(LRFS) rates were compared between the 2 treatment groups. Cox proportional hazards regression was performed to explore factors associated with DFS and LRFS.
Results
The 10-year local recurrence(LR) rates in the mastectomy and BCS plus adjuvant radiotherapy groups were 2.6% and 7.5%, respectively. There was no difference in the LR rate between the 2 groups. Furthermore the DFS rate was also similar between the mastectomy and BCS plus adjuvant radiotherapy groups. Based on the multivariable analysis, age and tumor grade were significantly correlated with the LRFS and DFS rates. In the subgroup analysis based on the factors of age and tumor grade, patients with a tumor grade of III who underwent mastectomy had better LRFS and DFS rates compared to those who received BCS plus radiotherapy.
Conclusion
In patients with DCIS, the long-term efficacy was similar between mastectomy and BCS followed by adjuvant radiotherapy. However, in the subgroup of patients with grade III tumors, mastectomy seems to offer a better LRFS and DFS than BCS plus radiotherapy.
... The clonal nature of LCIS has been established through loss of heterozygosity [31], comparative genomic hybridization [32][33][34] and single nucleotide polymorphism array [35] analyses. ALH and CLCIS are genetically similar, demonstrating recurrent deletions of 16q and gains of 1q with a similar pattern of unbalanced chromosomal aberrations [32,34]. ...
... Approximately 60-80% of ILC show somatic mutations in CDH1 and the initial identification of the same CDH1 mutations in synchronous LCIS and ILC provided direct support for LCIS being a precursor lesion to ILC [40]. The clonal origin for LCIS and synchronous ER-positive ILC has since been demonstrated in a number of other studies [33,35,41]. In addition, PLCIS and pleomorphic ILC have also been shown to share the same genetic aberrations [39]. ...
Lobular neoplasia (LN) is an atypical proliferation of small, dyscohesive epithelial cells within the terminal duct lobular unit (TDLU), with or without pagetoid extension and encompasses both lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH). LN is a non-obligate precursor of invasive breast carcinoma and the diagnosis of LN confers an increased risk of invasive carcinoma development, compared to the general population. Diagnostic challenges arise in the accurate classification of LCIS into classic, pleomorphic and florid subtypes, in distinguishing between LCIS and ductal carcinoma in situ (DCIS) and in the appropriate use and interpretation of E-cadherin immunohistochemistry. Due to the paucity of robust data on the natural history of LCIS, and hence its clinical significance, the management is often pragmatic rather than entirely evidence-based and requires a multidisciplinary approach. In this review, we discuss the clinicopathologic and molecular features of LCIS and address the key challenges that arise in the diagnosis and management of LCIS.
... Although LCIS has long been considered as a marker of increased breast cancer risk, some in the literature have proposed that a subset of LCIS may also be non-obligatory precursors of invasive breast cancer 4,5 . These assertions are supported by a growing body of research, which shows that LCIS and invasive lobular cancer share a unique pattern of genetic mutations and progressive alterations in gene expression [6][7][8][9][10] . However, the specific molecular factors leading to the increased risk of invasive breast cancer in LCIS patients remain largely unknown. ...
Certain matrix metalloproteinases (MMPs) have the ability to degrade collagen IV, a main component of the breast lobular basement membrane. In this cross-sectional study, we evaluated expression of MMPs 2, 9, and 14 and collagen IV in LCIS and adjacent normal breast tissue among LCIS patients without invasive breast cancer to determine whether expression differed between benign and preinvasive breast epithelial tissue. A total of 64 LCIS patients, diagnosed 2004–2014, were included; 44 had sufficient paired normal tissue for analysis. Marker epithelial expression was measured using immunofluorescence and quantified using the H score (MMPs) or pixel intensity (collagen IV). Associations were evaluated using the Spearman correlation or the Wilcoxon signed-rank test. In LCIS and normal tissue, there was a strong correlation between MMP2 and MMP14 expression (LCIS r = 0.69, normal r = 0.81, both P < 0.01). Other pairwise correlations were moderate to weak (range: LCIS r = 0.32–0.47, normal r = 0.19–0.32). For all markers, expression was lower in LCIS vs. normal tissue (all P ≤ 0.05). In sum, collagenase MMPs were expressed in normal breast and LCIS lesions of LCIS patients. However, expression was not higher in LCIS compared with normal tissue, suggesting collagenase MMP expression does not increase as breast tissue gains a more proliferative phenotype.
... Hence, similar DNA methylation and gene expression patterns might represent responses to similar environmental factors. Tumour evolution of subclones is hypothesized to lead to a mixed pattern of shared and independent CNAs and DNA mutations [157], which advocates the use of DNA-based data to assess clonality. On the other hand, tumours developing in the same genetic background and environmental setting have been hypothesized to accumulate more frequently similar patterns of DNA mutations and CNAs, despite emerging as independent tumours [152,158]. ...
... Hence, some artificial tumour pairs from different patients also showed statistical significance. Possible explanations could be intratumour heterogeneity, advanced accumulation of changes unique to the subclone, repeated occurrence of CNAs frequently identified in breast cancer [159][160][161], or technical artefacts increasing background noise [157]. Intratumour heterogeneity complicates clonality analyses due to biological differences in different parts of a tumour and subclone evolution, which presents a general disadvantage of bulk analyses. ...
Several gene signatures have been proposed in the past two decades to improve outcome prediction for breast cancer patients and to guide treatment decisions. Current treatment guidelines, however, primarily focus on established clinicopathological features. In Paper I, we identified a novel 18-marker gene expression signature predicting breast cancer-specific survival. The 18-marker signature was validated in three independent cohorts and showed increased predictive power over the clinically validated Oncotype Dx signature.
Despite increasing survival rates, about 6-23% of patients suffer from recurrences within five years of initial diagnosis indicating treatment failure. It is highly important to differentiate between clonally related recurrences and independent primary tumours due to potentially differing prognoses and treatment regimes. Currently, there is no consensus on how to define clonal relatedness between multiple tumours in the same patient. In Paper II, we identified the Similarity Index (SI) as the most reliable tool to classify tumour clonality.
The mammary gland is known to be highly sensitive to radiation, especially at a young age. In the years from 1920-1965, a total of 17,200 female Swedish infants were treated with ionizing radiation for skin haemangioma, resulting in an increased risk of developing breast cancer. In Paper III, we analysed breast tumours for genomic instability, which can be induced by ionizing radiation. Patients with higher absorbed doses to the breast exhibited increased genomic instability compared to patients exposed to lower absorbed doses. These results strongly suggest radiation-induced genomic instability as a biological link between ionizing radiation exposure at a young age and the increased breast cancer risk in subsequent decades.
In conclusion, this work highlights the importance of complementing established clinicopathological features with molecular biology and statistical models to improve breast cancer risk assessment and personalize treatment strategies.
Keywords: breast cancer, gene signature, molecular biomarkers, tumour clonality, genomic instability, Swedish haemangioma cohort
ISBN 978-91-7833-440-7 (PRINT)
ISBN 978-91-7833-441-4 (PDF)
http://hdl.handle.net/2077/59802
... LCIS and invasive lobular carcinomas (ILC) are phenotypically and genetically similar. Both lesions are preferentially of the luminal-A molecular subtype [i.e., estrogen receptor (ER)positive, HER2-negative, low-grade, and low-proliferation] and harbor recurrent gains of 1q and losses of 16q, encompassing the CDH1 gene locus, as well as recurrent CDH1 somatic mutations (1,(3)(4)(5)(6)(7). In fact, loss of E-cadherin, the protein product of the CDH1 gene, is a hallmark feature of these lesions (3,6) and has been shown to result in the development of ILCs in conditional mouse models (8). ...
... Previous studies have demonstrated that synchronous LCIS and invasive breast cancers may be clonally related and share a common ancestral lesion (4,7,10). In most studies, however, clonal relatedness was inferred using limited genomic information derived from copy-number (4) or targeted sequencing analyses (10). ...
... Previous studies have demonstrated that synchronous LCIS and invasive breast cancers may be clonally related and share a common ancestral lesion (4,7,10). In most studies, however, clonal relatedness was inferred using limited genomic information derived from copy-number (4) or targeted sequencing analyses (10). By combining copy-number and WES data, Begg and colleagues provided evidence of clonal relatedness between LCIS and associated lesions (7). ...
Purpose:
Lobular carcinoma in situ (LCIS) is a pre-invasive lesion of the breast. We sought to define its genomic landscape, whether intra-lesion genetic heterogeneity is present in LCIS, and the clonal relatedness between LCIS and invasive breast cancers.
Experimental design:
We reanalyzed whole-exome sequencing (WES) data and performed a targeted amplicon sequencing validation of mutations identified in 43 LCIS and 27 synchronous more clinically-advanced lesions from 24 patients (nine ductal carcinomas in situ (DCIS), 13 invasive lobular carcinomas (ILCs) and five invasive ductal carcinomas (IDCs)). Somatic genetic alterations, mutational signatures, clonal composition and phylogenetic trees were defined using validated computational methods.
Results:
WES of 43 LCIS lesions revealed a genomic profile similar to that previously reported for ILCs, with CDH1 mutations present in 81% of the lesions. Forty-two percent (18/43) of LCIS were found to be clonally-related to synchronous DCIS and/or ILCs, with clonal evolutionary patterns indicative of clonal selection and/or parallel/branched progression. Intra-lesion genetic heterogeneity was higher among LCIS clonally-related to DCIS/ILC than in those non-clonally related to DCIS/ILC. A shift from aging to APOBEC-related mutational processes was observed in the progression from LCIS to DCIS and/or ILC in a subset of cases.
Conclusions:
Our findings support the contention that LCIS has a repertoire of somatic genetic alterations similar to that of ILCs, and likely constitutes a non-obligate precursor of breast cancer. Intra-lesion genetic heterogeneity is observed in LCIS and should be considered in studies aiming to develop biomarkers of progression from LCIS to more advanced lesions.
... The understanding of lobular carcinoma in situ (LCIS) biology, and its clinical significance, has evolved [1][2][3]. At one end, instead of just being a risk factor for breast cancer, now, LCIS is considered a non-obligate precursor of invasive disease [1][2][3]. ...
... The understanding of lobular carcinoma in situ (LCIS) biology, and its clinical significance, has evolved [1][2][3]. At one end, instead of just being a risk factor for breast cancer, now, LCIS is considered a non-obligate precursor of invasive disease [1][2][3]. On the other end, recently, LCIS has been categorized as benign entity [4]. Many questions regarding LCIS, which may be important in management, remain unanswered: (1) Is there a clinically meaningful LCIS grading scheme? ...
... (2) What is the practical utility of the criteria applied for diagnosing so-called aggressive types of LCIS-pleomorphic (PLCIS) and florid LCIS (FLCIS)? (3) Can FLCIS and PLCIS be merged into one entity: aggressive/non-classical LCIS variants? ...
Morphological variants of lobular carcinoma in situ (LCIS) include classical- (CLCIS), pleomorphic- (PLCIS) and florid-type (FLCIS). Treatment guidelines suggest managing PLCIS and FLCIS like ductal carcinoma in situ (DCIS); therefore accurate identification of LCIS subtypes is critical. However significance of separating PLCIS from FLCIS is not clear. Also inter-observer agreement in identifying LCIS subtypes, using contemporary criteria, is not known. We aimed to evaluate inter-observer agreement amongst breast pathologists in diagnosing LCIS subtypes and use the agreement data to justify LCIS classification for management purposes. Six breast pathologists independently reviewed 50 hematoxylin and eosin stained slides comprised of a mix of LCIS subtypes. After reviewing published criteria participants diagnosed PLCIS, CLCIS and apocrine change in a marked region of interest and FLCIS based on entire section. PLCIS was identified in 8-37 slides with overall moderate agreement (Fleiss' κ =0.565) and pairwise κ (Cohen's) ranging from -.008 to 0.492. FLCIS was diagnosed in 15-26 slides with overall substantial agreement (Fleiss' κ =0.687) and pairwise κ ranging from -.068 to 0.706. Both FLCIS and PLCIS coexisted in 45% of slides with consensus on non-classical LCIS. Comedo-type necrosis (Odds ratio=5.5) and apoptosis (Odds ratio=1.8) predicted FLCIS. We found moderate and substantial agreement in diagnosing PLCIS and FLCIS respectively. Objective histological features linked with aggressive behavior were more frequent with FLCIS. PLCIS and FLCIS patterns frequently coexist, contain similar molecular aberrations, and are managed similarly (like DCIS); therefore combining FLCIS and PLCIS into one category (non-classical LCIS) should be considered.
... Women diagnosed with LCIS have a dramatically increased risk of invasive lobular cancer (ILC) and invasive ductal cancer (IDC) in either breast, with a relative risk that is eighteen and three to four times greater than that of the general population, respectively [6,14]. Despite the risk increasing role of LCIS, some groups suggested that it could not be considered as a precursor of ILC [15][16][17][18] while others thought that it was quite another story [19][20][21]. In addition, some researchers stated that patients with LCIS were less susceptible to subsequent invasive breast cancer (IBC) in comparison with those with DCIS [22] while some others draw a contrary conclusion [21]. ...
... It has been well-established that, like DCIS, LCIS is a risk factor for subsequent IBC. However, there is a dispute over the hypothesis that LCIS is a precursor of ILC [15][16][17][18][19][20][21]. Up to now, no consensus has been reached clinically on the treatment of LCIS. ...
Lobular carcinoma in situ (LCIS) represents 5.3% of in situ specimens, and is thought to carry a low risk for developing to the invasive lobular breast cancer (ILC). There is still no standard care approach for patients with LCIS. We aimed to define the impacts of surgical and radiation intervention on survival outcomes of LCIS. LCIS cases from 2004 to 2013 of the recent Surveillance, Epidemiology, and End Results (SEER) database were analyzed. Clinicopathologic features were analyzed in 16002 patients between 2004 and 2013. Treatment modalities included no surgery (NS), lumpectomy alone (LA), lumpectomy with radiation treatment (LRT), mastectomy alone (MA) and mastectomy with radiation treatment (MRT). The overall survival (OS) was calculated by the Kaplan-Meier method. Univariate and multivariate analyses were performed using the variables of treatment, race, hormone receptor status, grade and age. Among 16002 patients, median follow-up was 54 months. Patients treated with LA had superior OS for NS (P = 0.001), MA (P < 0.001) and MRT P = 0.018). LRT only had superior OS for MRT (P = 0.009). There was no statistically significance between LA and LRT (P = 0.317). Improved OS was also correlated with younger age (P < 0.001), progesterone receptor positive (P = 0.001). Black patients had the worst OS (P < 0.001). There was no obvious survival difference among grade groups (P = 0.536). The LCIS patients treated with LA or LRT had better survival comparing with other groups. Considering the medical expense and the risk of radiotherapy, LA may be the most appropriate therapy for patients with LCIS.
... In addition to being a marker of breast cancer risk, recent studies exploring the clonal relationship between LCIS and invasive lobular carcinoma (ILC) support the notion that LCIS may also represent a non-obligate precursor of invasive disease. [1][2][3][4][5][6] While the elevated risk of a subsequent breast malignancy has been well-established, little data exist on the long-term survival and breast cancer-related outcomes of women diagnosed with LCIS. Previous population-based studies comparing patients with LCIS with those with DCIS have reported a relative 5.3-fold increased probability of subsequent ILC, although patients with LCIS remain more predisposed to developing cancers of ductal histology overall. ...
... 8,18 Now, with accumulating evidence suggesting a clonal relationship between LCIS and synchronous ILC lesions has reinstated the notion that LCIS may additionally represent a non-obligate precursor of invasive disease. 1,5,19 While the results of the present study are correlative and cannot conclude a causal relationship, our data examining the distribution of subsequent invasive cancers stratified by histology lend support to the idea of LCIS being a nonobligate precursor of ILC. In addition to ILC being more prevalent in LCIS patients relative to the general population of women with de novo DCIS or invasive breast cancer, 7,20,21 our study finds that subsequent invasive lobular cancers preferentially lateralize to the ipsilateral breast of the index LCIS. ...
Purpose:
A diagnosis of lobular carcinoma in situ (LCIS) is associated with an increased risk of developing breast cancer, although little data exist on long-term patient outcomes, including those who develop subsequent breast malignancies.
Methods:
The Surveillance, Epidemiology, and End Results (SEER) database was used to identify women with a histological diagnosis of LCIS between 1983 and 2014. The incidence and clinicopathologic features of subsequent malignancies were then examined, and the Kaplan-Meier method and multivariable Cox PH regression used to obtain breast cancer-specific survival (BCSS) estimates and associated hazard ratios.
Results:
Overall, 19,462 women swith a mean age at LCIS diagnosis of 53.7 years, and a 10- and 20-year cumulative incidence of subsequent breast malignancy of 11.3% [95% confidence interval (CI) 10.7-11.9%] and 19.8% (95% CI 18.8-20.9) met the eligibility criteria. At a median follow-up of 8.1 years (range 0-30.9) a total of 1837 primary breast cancers were diagnosed, of which 55.2% were diagnosed in the ipsilateral breast. Most breast cancers were of low/intermediate grade, hormone receptor-positive, and diagnosed in early stages. Of subsequent malignancies, invasive ductal carcinoma (IDC) distributed equally across both breasts, whereas invasive lobular carcinoma (ILC) was more likely to present in the ipsilateral breast (69.0% ILC vs. 49.2% IDC; p < 0.001). On multivariable analysis, type of surgical treatment for LCIS had no affect on long-term survival (p = 0.44). The 10- and 20-year BCSS for women with LCIS was 98.9 and 96.3%, respectively.
Conclusion:
Women with LCIS who are diagnosed with a subsequent primary breast cancer are often diagnosed in early stages and have excellent BCSS.
