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Breast cancer precursors: diagnostic issues and current understanding on their pathogenesis
Pathology (April 2013) 45(3), pp. 209–213
PREMALIGNANCY
Breast cancer precursors: diagnostic issues and current understanding on their pathogenesis RAHMAWATI PARE*{, TAO YANG*{{, JOO-SHIK SHIN*{{, PUAY HOON TANô AND C. SOON LEE*{{§jj *Discipline of Pathology, School of Medicine, University of Western Sydney, {Cancer Pathology and Cell Biology Laboratory, Ingham Institute for Applied Medical Research, zDepartment of Anatomical Pathology, Liverpool Hospital, Sydney South West Pathology Service, §Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney South West Area Pathology Service, and jjCancer Pathology, Bosch Institute, University of Sydney, Sydney, New South Wales, Australia; ôDepartment of Pathology, Singapore General Hospital, Singapore
Summary The development of breast malignancy has been recognised to progress through a number of morphological precursor lesions. More recently, specific molecular alterations have been recognised in these precursor lesions. These changes appear to determine a specific malignant phenotype, which in turn, may realign the current opinion on the classification of breast cancer along molecular characteristics. This review will highlight the morphological features of these precursor lesions and their relationship to the complex molecular processes involved in their development. Abbreviations: ADH, atypical ductal hyperplasia; ALH, atypical lobular hyperplasia; CCL, columnar cell lesion; DCIS, ductal carcinoma in situ; FEA, flat epithelial atypia; LCIS, lobular carcinoma in situ; TLDU, terminal-duct lobular unit; UDH, usual ductal hyperplasia. Key words: ADH, atypical ductal hyperplasia, breast cancer, DCIS, DCIS, ductal carcinoma in situ, LCIS, lobular carcinoma in situ. Received 15 November, revised 19 December, accepted 20 December 2012
INTRODUCTION Breast cancer is the most commonly diagnosed cancer in females, comprising about 28.2% of all cancers diagnosed in Australia (http://www.aihw.gov.au/cancer/index.cfm). Breast cancer is rare before 25 years of age. Its incidence rises steadily after the third decade, peaks at the sixth decade and decreases slightly and plateaus in the eighth decade. Recent progress in the management of breast cancer patients and improvements in survival have been greatly contributed to by improved diagnostic screening and the elucidation of molecular mechanisms underpinning the disease, leading to availability of better treatment modalities. However, breast cancer precursors can pose diagnostic challenges and their molecular pathogenesis is still poorly understood. In this review, the diagnostic issues and some of the current understanding of the molecular mechanisms that may be responsible for their development will be discussed.
MORPHOLOGICAL FEATURES OF BREAST CANCER PRECURSORS The morphological features of precursor lesions of breast cancer are well-characterised. Morphologically, these lesions Print ISSN 0031-3025/Online ISSN 1465-3931 DOI: 10.1097/PAT.0b013e32835f2249
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are generally categorised according to histogenesis from the terminal-duct lobular unit (TDLU) of the breast. Intraductal precursors of breast cancer The intraductal precursors of breast cancer are a heterogenous group of lesions that include columnar cell lesion (CCL) with or without atypia, usual ductal hyperplasia (UDH) and atypical ductal hyperplasia (ADH). These lesions have an increased risk of developing, ranging from 1.2 to 5.1,2 CCLs are characterised by tall columnar epithelium with snouts, luminal secretions with or without microcalcifications, and a variable degree of hyperplasia and cytological atypia.3 CCLs are positive for low molecular weight cytokeratins and show limited and heterogeneous immunostaining for oestrogen receptor (ER) and progesterone receptor (PR). They are negative for basal cell markers such as CK5/6. UDH is defined by the presence of proliferating epithelium more than two cells thick and can range from mild to florid. Ductal architectural abnormalities, often resulting in distension of the duct lumen, may take the form of elongated or tufted papillary projections and cribriform masses with slit-like spaces at the periphery. The epithelial cell population has a polymorphic appearance with irregular arrangement of cells, and where they form bridges, the cells show a streaming pattern with cell nuclei arranged parallel to one another and with the cell bridges. The main diagnostic challenge for UDH is to distinguish it from ADH and low grade ductal carcinoma in situ (DCIS). ADH has epithelial proliferation characterised by architectural and cytological features that are atypical but fall short of the diagnosis of DCIS. Hence, the distinction between ADH and low grade DCIS can be very difficult. According to a recent review,4 ADH can be considered to have three diagnostic features: (1) uniform architecture that may be cribriform, micropapillary or solid, (2) cytological features characterised by small to medium cells that may be round, cuboidal or polygonal with evenly distributed nuclei, and (3) disease extent, in which the lesion is focal and small, occupying less than two separate duct spaces or up to 2 mm. DCIS, as the name implies, is a premalignant lesion with in situ proliferation of neoplastic epithelial cells usually within a duct, although the cells may spread into a lobule (‘lobular cancerisation’), with no invasion into the stroma surrounding the involved TDLU. DCIS can display a number of growth
2013 Royal College of Pathologists of Australasia
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patterns but details of these are well-described in the literature and are beyond the scope of this review. However, the diagnostic difficulty in distinguishing ADH from low grade DCIS, particularly the cribriform type, is highlighted. As noted in the aforementioned features of ADH, the architectural and cytological features of these two entities can be very similar, if not identical, and it is a matter of disease extent that separates them.4 On the other hand, high grade DCIS is readily recognised and its diagnosis is straightforward, with high reproducibility amongst practising diagnostic pathologists. The current internationally accepted grading system for DCIS is now based on a combination of nuclear grade and the presence or absence of luminal necrosis, which is more reproducible and, more importantly, appears to correlate with clinical outcomes.5–7 DCIS is classified as low, intermediate or high grade.4,7 Low grade DCIS is often characterised by micropapillary and cribriform growth patterns. The lesions show a population of uniformly appearing, evenly distributed cells with round, central nuclei, finely dispersed chromatin pattern, small nucleoli, and few mitoses. The growth patterns most often seen are cribriform, micropapillary and solid. Intermediate grade DCIS shows features between those of low and high grade DCIS and demonstrates micropapillary, cribriform, and often solid growth patterns. The cells show moderate nuclear pleomorphism. High grade DCIS often has a solid growth pattern with comedo necrosis, although other growth patterns can also be seen. It is composed of large cells with pleomorphic nuclei with coarse chromatin patterns and prominent, variably sized nucleoli. Many mitoses with abnormal forms are seen. From a diagnostic viewpoint, the growth patterns of DCIS and even nuclear grade can sometimes be heterogeneous but the grading should be based on the highest nuclear grade observed. Distinguishing between low grade DCIS and lobular carcinoma in situ (LCIS) can sometimes be difficult but this can usually be resolved by assessment for cellular cohesion with the presence of cell borders, absence of intracytoplasmic lumens and presence of E-cadherin immunostaining in DCIS.7 Another diagnostic issue is microinvasive carcinoma that can occasionally be seen in high grade DCIS, and its diagnosis can often be made by breach of the myoepithelial layer that can be highlighted by immunostaining for smooth muscle actin and p63.7 Lobular precursors of breast cancer The lobular precursors of breast cancer or lobular neoplasms are well described in the literature and consist of atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS).8 They are characterised by proliferation of small regular momomorphous, round to cuboidal or polygonal and dyscohesive epithelial cells that lack cell borders, with high nuclear:cytoplasmic (N:C) ratio. ALH is distinguished from LCIS by having a lesser proportion of the lobule involved (some authors refer to less than 50%)8,9 by these cells, less distension of the involved acini, incomplete obliteration of acinar lumens, less uniformity of cell types, more irregular spacing of tumour cells and more cellular cohesiveness. Pagetoid extension of the tumour cells along ducts can occur in both ALH and LCIS.8 Distinction of LCIS from low grade DCIS can be problematic and the diagnostic features for this distinction
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have been mentioned earlier. However, combined LCIS/DCIS can sometimes occur in the same TDLU, and the diagnosis of both should be described in the pathology report.
MOLECULAR EVENTS IN BREAST CANCER PRECURSORS In recent years, many studies have been focused on the molecular characteristics of benign breast diseases, precursor lesions, as well as invasive carcinomas of the breast. Not only have new molecular phenotypes of breast cancers been identified, a new multistep pathway of progression from precursor lesions to invasive carcinoma has been postulated.10 In clinical practice, breast cancers are categorised into either hormone receptor positive or negative, which appear to respond specifically to different types of adjuvant therapy. Recent molecular techniques such as gene profiling of breast cancers have identified specific molecular subtypes in addition to the traditionally recognised ER and PR status categories. The luminal A and luminal B groups form the major molecular subtype of hormone receptor positive cancers. On the other hand, the cancers that are HER2 negative and basal-like are the major subtypes among hormone receptor negative breast cancers. The luminal C and normal breast-like tumours that are described in some studies, however, are not well characterised.11–15 A significant molecular discovery in breast cancers is the identification of basal-like breast cancers, which are recognised by the World Health Organization (WHO) and are being variably applied into clinical practice. These tumours have similar molecular signatures but display heterogeneous histopathological characteristics, biomarker expression profiles, and clinical behaviour. The clinical outcome of patients with these tumours is variable and may not necessarily be as uniformly poor as first thought.16,17 Approximately 80% of BRCA1associated breast cancers have similar gene expression profiles as the basal-like cancer, and many sporadic basal-like breast cancers also show BRCA1 dysfunction.18,19 Based on the molecular characteristics, it is clear that breast cancer can no longer be considered as a single disease. Since the first set of data of molecular portraits and gene expression patterns of breast cancer published in 2000 by the Stanford group,12,20 it is apparent that breast cancers may have the same phenotypic histogenetic origin from the TDLU but are fundamentally a collection of multiple diseases that affect the same anatomical site.21,22 Hence, ER positive and ER negative breast cancers are essentially distinct diseases that have different molecular signatures. ER positive breast cancers have histological grade and proliferation that are strongly associated with the extent, complexity and type of genetic changes.10 These cancers usually share similar genetic alterations such as 16q deletion. On the other hand, ER negative breast cancers are usually high grade and comprise a group of diseases with more heterogeneous molecular alterations.23–31 Currently available evidence on the evolution of breast cancer suggests that it can be categorised into two groups based on histological grade: (1) a low grade group that encompasses low grade neoplasms, and (2) a high grade group that consists of high grade DCIS and high grade infiltrating carcinomas.10 Although there are many studies on the molecular characteristics of invasive breast cancer, the molecular events that occur during the development and progression of breast cancer precursors are less well established. Molecular mechanisms
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PREMALIGNANCY IN BREAST
mediating the progression of in situ carcinoma to infiltrating breast cancer remain largely unknown. Traditionally, the multistep progression pathway of breast cancer is assumed to be similar in concept to the Vogelstein model for colorectal cancer. In brief, initial alterations of epithelial cells in the TDLU transform to UDH with recognisable morphological features, then progress to ADH with involvement of a part of the TDLU, followed by low grade DCIS in which the entire duct is involved. At this stage, further progression is ensured by acquisition of genetic and epigenetic alterations resulting in the progression to high grade DCIS, and subsequent invasive carcinoma. A similar multistep process is also believed to occur in invasive lobular carcinoma. The development of invasive ductal carcinoma of the breast was previously thought to result from sequential progression from hyperplasia to ADH to DCIS to invasive carcinoma pathway.32,33 However, emerging evidence from genomic and transcriptomic studies suggests that histologically low and high grade in situ lesions and their respective invasive counterparts are essentially different.30,34–36 It is now recognised that low grade and high grade invasive breast carcinomas show very different molecular alterations. There are data showing that low grade DCIS and high grade DCIS are different diseases.24,37 The low grade in situ breast lesions are characterised by the deletion of chromosomal 16q (>80%) and gains of 1q (>75%) and 16p (15%).24,25,27,30,36,38–40 However, similar genetic alterations are less common in high grade DCIS, in which heterogeneous genetic profiles including alterations at 13q, 17q, and 20q are more frequent.10 High grade DCIS and its invasive counterpart have more complexity in genomic alterations, with deletions of 16q found in less than 30% of cases. The absence of 16q deletions in the majority of high grade breast cancers appears to indicate that most high grade DCIS arise either de novo or from a precursor lesion other than ADH and/or low grade DCIS.10 The breast cancer precursor ADH shares many similar molecular features with low grade DCIS41 and low grade invasive ductal carcinoma. Flat epithelial atypia (FEA), another precursor lesion, shares similar molecular features with tubular carcinoma, a variant of low grade breast carcinoma.24 The different molecular signatures of low grade neoplasia and high grade neoplasia families also closely correlate with clinical and histological findings, in which high grade DCIS is usually associated with high grade breast carcinoma, and low grade DCIS associated with low grade invasive carcinoma. In tubular carcinomas, the precursor component is most likely to be FEA or low grade DCIS with cribriform pattern. The similarity in growth patterns, hormone receptor status and gene expression profiles strongly suggests that low grade DCIS is a precursor of low grade invasive ductal carcinoma, whilst high grade DCIS is a precursor of high grade invasive ductal carcinoma.24,37 ADH is one of the precursor lesions of low grade DCIS and invasive carcinoma, as classified in the traditional progression pathways. The molecular similarity of ADH and low grade DCIS has been confirmed by genetic analyses showing allelic imbalances at similar frequencies in both lesions.10 Furthermore, allelic imbalances were concordant in matched sample studies of ADH, low grade DCIS and low grade breast cancer, indicating ADH is in fact a neoplastic lesion with similar molecular characteristics to low grade DCIS. With these molecular characteristics, it is not difficult to accept that ADH plays an unequivocal role in the progression of breast cancer42,43 along similar molecular pathways. Similar to other low grade
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lesions, ADH demonstrates the low grade family’s molecular signature with recurrent deletion of 16q and 17p and gains of 1q.42–44 Comparative genomic hybridisation studies have confirmed both ADH and low grade DCIS to be clonal.44–46 Based on the similarity of the molecular alterations, ADH and low grade DCIS may be considered a continuum of the same disease, distinguished arbitrarily by the extent of ductal involvement or lesional size, an approach adopted to avoid overtreatment and classification of small low grade lesions as DCIS. CCLs (including those with atypia, FEA) have been shown to be associated with an increased risk of development of breast cancer. Recent data suggest that the majority of CCLs are also clonal,36,46–49 similar to other low grade neoplasms. Although there are various degrees of architectural abnormality and cytological atypia encompassing this group of interrelated lesions, molecular analysis has shown that the degree of genetic alterations correspond to the degree of abnormality in this disease spectrum. Similar to ADH and low grade DCIS, CCLs are also neoplastic rather than hyperplastic lesions.10 The molecular alterations observed in CCLs are identical to those seen in ADH and low grade DCIS.10 With an increased number of gene profiling studies, it has become clear that a group of low grade lesions show striking similarity in terms of genetic alterations. This group of lesions include CCLs, ADH, low grade DCIS, as well as FEA and LCIS, which are also frequently found in association with low grade invasive breast cancer. It is postulated that they may constitute a family of first morphologically identifiable precursors of low grade breast cancers,10,36,50,51 the so-called low grade breast neoplasia family. On the other hand, a group of benign lesions shows no evidence of clonal numerical chromosomal alteration based on molecular study. Only in the minority of UDH can some genetic alterations be detected; however, they are usually sporadic and are not present in the same region of invasive disease. Molecular studies on radial scar and apocrine lesions are not entirely conclusive with no specific molecular characteristics, although there are clinical studies suggesting a possible increased risk of development of invasive breast cancer.10 It is understandable that there may be genetic alterations occurring even in normal breast tissues during life, as in any other type of tissues. These alterations are not significant and do not show overlap with specific genetic alterations seen in DCIS and invasive ductal carcinoma. However, the presence of molecular alterations is not necessarily sufficient to suggest that these cells are non-obligate precursors. It is worth noting that LOH in normal TDLUs does not seem increased in prevalence in breast tissues adjacent to breast carcinoma.52 By gene profiling, synchronous DCIS and invasive breast cancer are found to have similar molecular profiles,53 particularly those of similar histological grade.54 However, in the group with pure DCIS and invasive ductal carcinoma harvested from separate patients, gene profiling shows very different profiles, indicating that there are also unique patterns of gene expression in these two stages of breast cancer. When comparing gene expression profiles of DCIS and invasive breast cancer, Lee and colleagues identified 470 differentially expressed genes, of which 74 genes were found to be particularly significant with overlapping findings in nine other similar studies in the literature.53 The progression of DCIS to invasive breast cancer was studied in vivo using DCIS.com cell line engineered to express specific genes into
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a mammary intraductal DCIS xenograft model. Using lentiviral mediated RNA interference technique, progression of xenografts to invasive cancer was found to be dramatically increased by suppressing four genes that were usually elevated in clinical samples of DCIS, which included a protease inhibitor (CSTA) and genes involved in cell adhesion and signalling (FAT1, DST, and TMEM45A), and strongly suggested that they normally function to suppress progression. When matched by histological grade and hormone receptor status, in situ and invasive breast cancers of either low or high grade show similar genetic profiles,24,43,55 i.e., low grade DCIS shares similar molecular signatures with low grade invasive ductal carcinoma, and high grade DCIS is similar to high grade invasive carcinoma. Molecular analysis has failed to reveal any specific difference between in situ and invasive carcinoma in both categories. No specific molecular events have so far been identified to illustrate the progression from in situ to invasive carcinoma, and this process of progression may not necessarily be determined by specific genetic alterations or gene expression patterns. There may be multiple genetic or epigenetic aberrations occurring simultaneously in progression in each individual case, possibly with distinct genetic aberrations.
CONCLUSION It is now accepted that progression from in situ to invasive breast cancer involves a number of complex molecular and cellular processses – the in situ tumours themselves are preceded by additional precursor lesions. A simple linear model is not sufficient to explain the phenomenon that involves multiple steps of progression, and undoubtedly oversimplifies a complex process. It is likely that in situ neoplasia with distinct molecular profiles progress to invasive breast cancer through the acquisition of specific genetic or epigenetic alterations. Further study in this field, especially establishing in vivo models of precursor lesions, may perhaps provide better insight into the progression to invasive breast carcinoma. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Address for correspondence: Professor C. S. Lee, Department of Anatomical Pathology, Liverpool Hospital, Sydney South West Area Pathology Service, Locked Mail Bag 7090, Liverpool BC, NSW 1871, Australia. E-mail: soon. [email protected]
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Breast cancer precursors: diagnostic issues and current understanding on their pathogenesis RAHMAWATI PARE*{, TAO YANG*{{, JOO-SHIK SHIN*{{, PUAY HOON TANô AND C. SOON LEE*{{§jj *Discipline of Pathology, School of Medicine, University of Western Sydney, {Cancer Pathology and Cell Biology Laboratory, Ingham Institute for Applied Medical Research, zDepartment of Anatomical Pathology, Liverpool Hospital, Sydney South West Pathology Service, §Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney South West Area Pathology Service, and jjCancer Pathology, Bosch Institute, University of Sydney, Sydney, New South Wales, Australia; ôDepartment of Pathology, Singapore General Hospital, Singapore
Summary The development of breast malignancy has been recognised to progress through a number of morphological precursor lesions. More recently, specific molecular alterations have been recognised in these precursor lesions. These changes appear to determine a specific malignant phenotype, which in turn, may realign the current opinion on the classification of breast cancer along molecular characteristics. This review will highlight the morphological features of these precursor lesions and their relationship to the complex molecular processes involved in their development. Abbreviations: ADH, atypical ductal hyperplasia; ALH, atypical lobular hyperplasia; CCL, columnar cell lesion; DCIS, ductal carcinoma in situ; FEA, flat epithelial atypia; LCIS, lobular carcinoma in situ; TLDU, terminal-duct lobular unit; UDH, usual ductal hyperplasia. Key words: ADH, atypical ductal hyperplasia, breast cancer, DCIS, DCIS, ductal carcinoma in situ, LCIS, lobular carcinoma in situ. Received 15 November, revised 19 December, accepted 20 December 2012
INTRODUCTION Breast cancer is the most commonly diagnosed cancer in females, comprising about 28.2% of all cancers diagnosed in Australia (http://www.aihw.gov.au/cancer/index.cfm). Breast cancer is rare before 25 years of age. Its incidence rises steadily after the third decade, peaks at the sixth decade and decreases slightly and plateaus in the eighth decade. Recent progress in the management of breast cancer patients and improvements in survival have been greatly contributed to by improved diagnostic screening and the elucidation of molecular mechanisms underpinning the disease, leading to availability of better treatment modalities. However, breast cancer precursors can pose diagnostic challenges and their molecular pathogenesis is still poorly understood. In this review, the diagnostic issues and some of the current understanding of the molecular mechanisms that may be responsible for their development will be discussed.
MORPHOLOGICAL FEATURES OF BREAST CANCER PRECURSORS The morphological features of precursor lesions of breast cancer are well-characterised. Morphologically, these lesions Print ISSN 0031-3025/Online ISSN 1465-3931 DOI: 10.1097/PAT.0b013e32835f2249
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are generally categorised according to histogenesis from the terminal-duct lobular unit (TDLU) of the breast. Intraductal precursors of breast cancer The intraductal precursors of breast cancer are a heterogenous group of lesions that include columnar cell lesion (CCL) with or without atypia, usual ductal hyperplasia (UDH) and atypical ductal hyperplasia (ADH). These lesions have an increased risk of developing, ranging from 1.2 to 5.1,2 CCLs are characterised by tall columnar epithelium with snouts, luminal secretions with or without microcalcifications, and a variable degree of hyperplasia and cytological atypia.3 CCLs are positive for low molecular weight cytokeratins and show limited and heterogeneous immunostaining for oestrogen receptor (ER) and progesterone receptor (PR). They are negative for basal cell markers such as CK5/6. UDH is defined by the presence of proliferating epithelium more than two cells thick and can range from mild to florid. Ductal architectural abnormalities, often resulting in distension of the duct lumen, may take the form of elongated or tufted papillary projections and cribriform masses with slit-like spaces at the periphery. The epithelial cell population has a polymorphic appearance with irregular arrangement of cells, and where they form bridges, the cells show a streaming pattern with cell nuclei arranged parallel to one another and with the cell bridges. The main diagnostic challenge for UDH is to distinguish it from ADH and low grade ductal carcinoma in situ (DCIS). ADH has epithelial proliferation characterised by architectural and cytological features that are atypical but fall short of the diagnosis of DCIS. Hence, the distinction between ADH and low grade DCIS can be very difficult. According to a recent review,4 ADH can be considered to have three diagnostic features: (1) uniform architecture that may be cribriform, micropapillary or solid, (2) cytological features characterised by small to medium cells that may be round, cuboidal or polygonal with evenly distributed nuclei, and (3) disease extent, in which the lesion is focal and small, occupying less than two separate duct spaces or up to 2 mm. DCIS, as the name implies, is a premalignant lesion with in situ proliferation of neoplastic epithelial cells usually within a duct, although the cells may spread into a lobule (‘lobular cancerisation’), with no invasion into the stroma surrounding the involved TDLU. DCIS can display a number of growth
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patterns but details of these are well-described in the literature and are beyond the scope of this review. However, the diagnostic difficulty in distinguishing ADH from low grade DCIS, particularly the cribriform type, is highlighted. As noted in the aforementioned features of ADH, the architectural and cytological features of these two entities can be very similar, if not identical, and it is a matter of disease extent that separates them.4 On the other hand, high grade DCIS is readily recognised and its diagnosis is straightforward, with high reproducibility amongst practising diagnostic pathologists. The current internationally accepted grading system for DCIS is now based on a combination of nuclear grade and the presence or absence of luminal necrosis, which is more reproducible and, more importantly, appears to correlate with clinical outcomes.5–7 DCIS is classified as low, intermediate or high grade.4,7 Low grade DCIS is often characterised by micropapillary and cribriform growth patterns. The lesions show a population of uniformly appearing, evenly distributed cells with round, central nuclei, finely dispersed chromatin pattern, small nucleoli, and few mitoses. The growth patterns most often seen are cribriform, micropapillary and solid. Intermediate grade DCIS shows features between those of low and high grade DCIS and demonstrates micropapillary, cribriform, and often solid growth patterns. The cells show moderate nuclear pleomorphism. High grade DCIS often has a solid growth pattern with comedo necrosis, although other growth patterns can also be seen. It is composed of large cells with pleomorphic nuclei with coarse chromatin patterns and prominent, variably sized nucleoli. Many mitoses with abnormal forms are seen. From a diagnostic viewpoint, the growth patterns of DCIS and even nuclear grade can sometimes be heterogeneous but the grading should be based on the highest nuclear grade observed. Distinguishing between low grade DCIS and lobular carcinoma in situ (LCIS) can sometimes be difficult but this can usually be resolved by assessment for cellular cohesion with the presence of cell borders, absence of intracytoplasmic lumens and presence of E-cadherin immunostaining in DCIS.7 Another diagnostic issue is microinvasive carcinoma that can occasionally be seen in high grade DCIS, and its diagnosis can often be made by breach of the myoepithelial layer that can be highlighted by immunostaining for smooth muscle actin and p63.7 Lobular precursors of breast cancer The lobular precursors of breast cancer or lobular neoplasms are well described in the literature and consist of atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS).8 They are characterised by proliferation of small regular momomorphous, round to cuboidal or polygonal and dyscohesive epithelial cells that lack cell borders, with high nuclear:cytoplasmic (N:C) ratio. ALH is distinguished from LCIS by having a lesser proportion of the lobule involved (some authors refer to less than 50%)8,9 by these cells, less distension of the involved acini, incomplete obliteration of acinar lumens, less uniformity of cell types, more irregular spacing of tumour cells and more cellular cohesiveness. Pagetoid extension of the tumour cells along ducts can occur in both ALH and LCIS.8 Distinction of LCIS from low grade DCIS can be problematic and the diagnostic features for this distinction
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have been mentioned earlier. However, combined LCIS/DCIS can sometimes occur in the same TDLU, and the diagnosis of both should be described in the pathology report.
MOLECULAR EVENTS IN BREAST CANCER PRECURSORS In recent years, many studies have been focused on the molecular characteristics of benign breast diseases, precursor lesions, as well as invasive carcinomas of the breast. Not only have new molecular phenotypes of breast cancers been identified, a new multistep pathway of progression from precursor lesions to invasive carcinoma has been postulated.10 In clinical practice, breast cancers are categorised into either hormone receptor positive or negative, which appear to respond specifically to different types of adjuvant therapy. Recent molecular techniques such as gene profiling of breast cancers have identified specific molecular subtypes in addition to the traditionally recognised ER and PR status categories. The luminal A and luminal B groups form the major molecular subtype of hormone receptor positive cancers. On the other hand, the cancers that are HER2 negative and basal-like are the major subtypes among hormone receptor negative breast cancers. The luminal C and normal breast-like tumours that are described in some studies, however, are not well characterised.11–15 A significant molecular discovery in breast cancers is the identification of basal-like breast cancers, which are recognised by the World Health Organization (WHO) and are being variably applied into clinical practice. These tumours have similar molecular signatures but display heterogeneous histopathological characteristics, biomarker expression profiles, and clinical behaviour. The clinical outcome of patients with these tumours is variable and may not necessarily be as uniformly poor as first thought.16,17 Approximately 80% of BRCA1associated breast cancers have similar gene expression profiles as the basal-like cancer, and many sporadic basal-like breast cancers also show BRCA1 dysfunction.18,19 Based on the molecular characteristics, it is clear that breast cancer can no longer be considered as a single disease. Since the first set of data of molecular portraits and gene expression patterns of breast cancer published in 2000 by the Stanford group,12,20 it is apparent that breast cancers may have the same phenotypic histogenetic origin from the TDLU but are fundamentally a collection of multiple diseases that affect the same anatomical site.21,22 Hence, ER positive and ER negative breast cancers are essentially distinct diseases that have different molecular signatures. ER positive breast cancers have histological grade and proliferation that are strongly associated with the extent, complexity and type of genetic changes.10 These cancers usually share similar genetic alterations such as 16q deletion. On the other hand, ER negative breast cancers are usually high grade and comprise a group of diseases with more heterogeneous molecular alterations.23–31 Currently available evidence on the evolution of breast cancer suggests that it can be categorised into two groups based on histological grade: (1) a low grade group that encompasses low grade neoplasms, and (2) a high grade group that consists of high grade DCIS and high grade infiltrating carcinomas.10 Although there are many studies on the molecular characteristics of invasive breast cancer, the molecular events that occur during the development and progression of breast cancer precursors are less well established. Molecular mechanisms
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mediating the progression of in situ carcinoma to infiltrating breast cancer remain largely unknown. Traditionally, the multistep progression pathway of breast cancer is assumed to be similar in concept to the Vogelstein model for colorectal cancer. In brief, initial alterations of epithelial cells in the TDLU transform to UDH with recognisable morphological features, then progress to ADH with involvement of a part of the TDLU, followed by low grade DCIS in which the entire duct is involved. At this stage, further progression is ensured by acquisition of genetic and epigenetic alterations resulting in the progression to high grade DCIS, and subsequent invasive carcinoma. A similar multistep process is also believed to occur in invasive lobular carcinoma. The development of invasive ductal carcinoma of the breast was previously thought to result from sequential progression from hyperplasia to ADH to DCIS to invasive carcinoma pathway.32,33 However, emerging evidence from genomic and transcriptomic studies suggests that histologically low and high grade in situ lesions and their respective invasive counterparts are essentially different.30,34–36 It is now recognised that low grade and high grade invasive breast carcinomas show very different molecular alterations. There are data showing that low grade DCIS and high grade DCIS are different diseases.24,37 The low grade in situ breast lesions are characterised by the deletion of chromosomal 16q (>80%) and gains of 1q (>75%) and 16p (15%).24,25,27,30,36,38–40 However, similar genetic alterations are less common in high grade DCIS, in which heterogeneous genetic profiles including alterations at 13q, 17q, and 20q are more frequent.10 High grade DCIS and its invasive counterpart have more complexity in genomic alterations, with deletions of 16q found in less than 30% of cases. The absence of 16q deletions in the majority of high grade breast cancers appears to indicate that most high grade DCIS arise either de novo or from a precursor lesion other than ADH and/or low grade DCIS.10 The breast cancer precursor ADH shares many similar molecular features with low grade DCIS41 and low grade invasive ductal carcinoma. Flat epithelial atypia (FEA), another precursor lesion, shares similar molecular features with tubular carcinoma, a variant of low grade breast carcinoma.24 The different molecular signatures of low grade neoplasia and high grade neoplasia families also closely correlate with clinical and histological findings, in which high grade DCIS is usually associated with high grade breast carcinoma, and low grade DCIS associated with low grade invasive carcinoma. In tubular carcinomas, the precursor component is most likely to be FEA or low grade DCIS with cribriform pattern. The similarity in growth patterns, hormone receptor status and gene expression profiles strongly suggests that low grade DCIS is a precursor of low grade invasive ductal carcinoma, whilst high grade DCIS is a precursor of high grade invasive ductal carcinoma.24,37 ADH is one of the precursor lesions of low grade DCIS and invasive carcinoma, as classified in the traditional progression pathways. The molecular similarity of ADH and low grade DCIS has been confirmed by genetic analyses showing allelic imbalances at similar frequencies in both lesions.10 Furthermore, allelic imbalances were concordant in matched sample studies of ADH, low grade DCIS and low grade breast cancer, indicating ADH is in fact a neoplastic lesion with similar molecular characteristics to low grade DCIS. With these molecular characteristics, it is not difficult to accept that ADH plays an unequivocal role in the progression of breast cancer42,43 along similar molecular pathways. Similar to other low grade
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lesions, ADH demonstrates the low grade family’s molecular signature with recurrent deletion of 16q and 17p and gains of 1q.42–44 Comparative genomic hybridisation studies have confirmed both ADH and low grade DCIS to be clonal.44–46 Based on the similarity of the molecular alterations, ADH and low grade DCIS may be considered a continuum of the same disease, distinguished arbitrarily by the extent of ductal involvement or lesional size, an approach adopted to avoid overtreatment and classification of small low grade lesions as DCIS. CCLs (including those with atypia, FEA) have been shown to be associated with an increased risk of development of breast cancer. Recent data suggest that the majority of CCLs are also clonal,36,46–49 similar to other low grade neoplasms. Although there are various degrees of architectural abnormality and cytological atypia encompassing this group of interrelated lesions, molecular analysis has shown that the degree of genetic alterations correspond to the degree of abnormality in this disease spectrum. Similar to ADH and low grade DCIS, CCLs are also neoplastic rather than hyperplastic lesions.10 The molecular alterations observed in CCLs are identical to those seen in ADH and low grade DCIS.10 With an increased number of gene profiling studies, it has become clear that a group of low grade lesions show striking similarity in terms of genetic alterations. This group of lesions include CCLs, ADH, low grade DCIS, as well as FEA and LCIS, which are also frequently found in association with low grade invasive breast cancer. It is postulated that they may constitute a family of first morphologically identifiable precursors of low grade breast cancers,10,36,50,51 the so-called low grade breast neoplasia family. On the other hand, a group of benign lesions shows no evidence of clonal numerical chromosomal alteration based on molecular study. Only in the minority of UDH can some genetic alterations be detected; however, they are usually sporadic and are not present in the same region of invasive disease. Molecular studies on radial scar and apocrine lesions are not entirely conclusive with no specific molecular characteristics, although there are clinical studies suggesting a possible increased risk of development of invasive breast cancer.10 It is understandable that there may be genetic alterations occurring even in normal breast tissues during life, as in any other type of tissues. These alterations are not significant and do not show overlap with specific genetic alterations seen in DCIS and invasive ductal carcinoma. However, the presence of molecular alterations is not necessarily sufficient to suggest that these cells are non-obligate precursors. It is worth noting that LOH in normal TDLUs does not seem increased in prevalence in breast tissues adjacent to breast carcinoma.52 By gene profiling, synchronous DCIS and invasive breast cancer are found to have similar molecular profiles,53 particularly those of similar histological grade.54 However, in the group with pure DCIS and invasive ductal carcinoma harvested from separate patients, gene profiling shows very different profiles, indicating that there are also unique patterns of gene expression in these two stages of breast cancer. When comparing gene expression profiles of DCIS and invasive breast cancer, Lee and colleagues identified 470 differentially expressed genes, of which 74 genes were found to be particularly significant with overlapping findings in nine other similar studies in the literature.53 The progression of DCIS to invasive breast cancer was studied in vivo using DCIS.com cell line engineered to express specific genes into
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a mammary intraductal DCIS xenograft model. Using lentiviral mediated RNA interference technique, progression of xenografts to invasive cancer was found to be dramatically increased by suppressing four genes that were usually elevated in clinical samples of DCIS, which included a protease inhibitor (CSTA) and genes involved in cell adhesion and signalling (FAT1, DST, and TMEM45A), and strongly suggested that they normally function to suppress progression. When matched by histological grade and hormone receptor status, in situ and invasive breast cancers of either low or high grade show similar genetic profiles,24,43,55 i.e., low grade DCIS shares similar molecular signatures with low grade invasive ductal carcinoma, and high grade DCIS is similar to high grade invasive carcinoma. Molecular analysis has failed to reveal any specific difference between in situ and invasive carcinoma in both categories. No specific molecular events have so far been identified to illustrate the progression from in situ to invasive carcinoma, and this process of progression may not necessarily be determined by specific genetic alterations or gene expression patterns. There may be multiple genetic or epigenetic aberrations occurring simultaneously in progression in each individual case, possibly with distinct genetic aberrations.
CONCLUSION It is now accepted that progression from in situ to invasive breast cancer involves a number of complex molecular and cellular processses – the in situ tumours themselves are preceded by additional precursor lesions. A simple linear model is not sufficient to explain the phenomenon that involves multiple steps of progression, and undoubtedly oversimplifies a complex process. It is likely that in situ neoplasia with distinct molecular profiles progress to invasive breast cancer through the acquisition of specific genetic or epigenetic alterations. Further study in this field, especially establishing in vivo models of precursor lesions, may perhaps provide better insight into the progression to invasive breast carcinoma. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Address for correspondence: Professor C. S. Lee, Department of Anatomical Pathology, Liverpool Hospital, Sydney South West Area Pathology Service, Locked Mail Bag 7090, Liverpool BC, NSW 1871, Australia. E-mail: soon. [email protected]
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