Molecular Drivers of Lobular Carcinoma in Situ
Molecular Drivers of Lobular Carcinoma in Situ
Lobular carcinoma in situ (LCIS) is considered to be a risk factor for the development of invasive breast carcinoma, but it may also be a non-obligate precursor to invasive lobular carcinoma (ILC). Many LCIS lesions do not progress to ILC, and the molecular changes that are necessary for progression from LCIS to ILC are poorly understood. Disruption in the E-cadherin complex is the hallmark of lobular lesions, but other signaling molecules, such as PIK3CA and c-src, are consistently altered in LCIS. This review focuses on the molecular drivers of lobular carcinoma, a more complete understanding of which may give perspective on which LCIS lesions progress, and which will not, thus having immense clinical implications.
Lobular carcinoma in situ (LCIS) has long been considered a risk factor for the future development, in either breast, of invasive breast carcinoma (IBC), but recent evidence suggests that LCIS may also be a non-obligate precursor to IBC, and more specifically to invasive lobular carcinoma (ILC).
LCIS is rarely detected by physical examination, nor does it have specific diagnostic mammographic findings. Currently about 0.5 to 3.9 % of image-guided core needle biopsies incidentally identify LCIS and, as mammographic technology improves, the incidence of LCIS is rising. Patients diagnosed with LCIS have an 8- to 10-fold increased lifetime risk of developing breast cancer, compared with women without this diagnosis. The likelihood of developing IBC increases by about 1 % every year after LCIS diagnosis - with a 13 % risk after 10 years and a 21 to 26 % risk after 20 years. In a recent subgroup analysis of participants of the Canadian National Breast Screening Study, the cumulative probability of subsequent breast cancer occurrence 5 years after diagnosis was lower for LCIS, compared with ductal carcinoma in situ (DCIS) (5.7 % versus 11.4 %, respectively); however, by 20 years after the diagnosis of LCIS or DCIS, rates of IBC were equivalent (21.3 % and 19 %, respectively).
LCIS was originally described as 'lobular' because the lesions appeared most often in the terminal duct lobular units (TDLUs), whereas ductal lesions appeared most often in the mammary ducts. However, it is now understood that all pre-invasive lesions originate from the TDLUs but the terms 'lobular' and 'ductal' have persisted.
LCIS is believed to arise from atypical lobular hyperplasia (ALH), a pre-invasive lesion with morphological features similar to LCIS, except with smaller, less distended acini. ALH and LCIS share similar chromosomal changes and molecular features. Since the factors that distinguish ALH from LCIS are somewhat subjective, the term lobular neoplasia (LN) has been adopted by many to encompass all pre-invasive lobular disease. The most well-studied characteristic of LN is loss of E-cadherin, and this is clinically used to differentiate lobular from ductal lesions. Herein, we review the studies to date that focus on the molecular mechanisms of LCIS. Gaining a better understanding of the pathways underlying LCIS and its non-obligate progression to IBC might allow the development of predictive tools that would refine the management of this challenging clinical entity.
Abstract and Introduction
Abstract
Lobular carcinoma in situ (LCIS) is considered to be a risk factor for the development of invasive breast carcinoma, but it may also be a non-obligate precursor to invasive lobular carcinoma (ILC). Many LCIS lesions do not progress to ILC, and the molecular changes that are necessary for progression from LCIS to ILC are poorly understood. Disruption in the E-cadherin complex is the hallmark of lobular lesions, but other signaling molecules, such as PIK3CA and c-src, are consistently altered in LCIS. This review focuses on the molecular drivers of lobular carcinoma, a more complete understanding of which may give perspective on which LCIS lesions progress, and which will not, thus having immense clinical implications.
Introduction
Lobular carcinoma in situ (LCIS) has long been considered a risk factor for the future development, in either breast, of invasive breast carcinoma (IBC), but recent evidence suggests that LCIS may also be a non-obligate precursor to IBC, and more specifically to invasive lobular carcinoma (ILC).
LCIS is rarely detected by physical examination, nor does it have specific diagnostic mammographic findings. Currently about 0.5 to 3.9 % of image-guided core needle biopsies incidentally identify LCIS and, as mammographic technology improves, the incidence of LCIS is rising. Patients diagnosed with LCIS have an 8- to 10-fold increased lifetime risk of developing breast cancer, compared with women without this diagnosis. The likelihood of developing IBC increases by about 1 % every year after LCIS diagnosis - with a 13 % risk after 10 years and a 21 to 26 % risk after 20 years. In a recent subgroup analysis of participants of the Canadian National Breast Screening Study, the cumulative probability of subsequent breast cancer occurrence 5 years after diagnosis was lower for LCIS, compared with ductal carcinoma in situ (DCIS) (5.7 % versus 11.4 %, respectively); however, by 20 years after the diagnosis of LCIS or DCIS, rates of IBC were equivalent (21.3 % and 19 %, respectively).
LCIS was originally described as 'lobular' because the lesions appeared most often in the terminal duct lobular units (TDLUs), whereas ductal lesions appeared most often in the mammary ducts. However, it is now understood that all pre-invasive lesions originate from the TDLUs but the terms 'lobular' and 'ductal' have persisted.
LCIS is believed to arise from atypical lobular hyperplasia (ALH), a pre-invasive lesion with morphological features similar to LCIS, except with smaller, less distended acini. ALH and LCIS share similar chromosomal changes and molecular features. Since the factors that distinguish ALH from LCIS are somewhat subjective, the term lobular neoplasia (LN) has been adopted by many to encompass all pre-invasive lobular disease. The most well-studied characteristic of LN is loss of E-cadherin, and this is clinically used to differentiate lobular from ductal lesions. Herein, we review the studies to date that focus on the molecular mechanisms of LCIS. Gaining a better understanding of the pathways underlying LCIS and its non-obligate progression to IBC might allow the development of predictive tools that would refine the management of this challenging clinical entity.
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