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Keywords:

  • atypical lobular hyperplasia;
  • invasive lobular carcinoma;
  • lobular carcinoma in situ;
  • lobular neoplasia

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical considerations
  5. The histopathology of lobular neoplasia
  6. Molecular pathology and cytogenetics
  7. Acknowledgements
  8. References

Lobular neoplasia of the breast represents a group of related malignancies with clinical implications ranging from risk lesions [atypical lobular hyperplasia and lobular carcinoma in situ (LCIS)] through to aggressive invasive lesions, notably invasive pleomorphic lobular carcinoma. The diversity in lobular carcinoma is evident at the morphological level, at the molecular marker level and in cytogenetic profiles. Research in these areas is already changing the face of the disease group, for example suggesting that some lobular and ductal carcinomas are closely related and even that one of the lobular group, the tubulo-lobular carcinomas, should, in fact, be regarded as a ductal cancer. More research is required to understand the long-term pathogenic implications of a diagnosis of in situ lobular neoplasia, particularly pleomorphic LCIS, and to understand the genetics behind the well-recognized high risk of bilateral disease. For invasive carcinoma, molecular studies will allow refinement of therapy and the possibility of novel targeted therapies, for example directed against fibroblast growth factor receptor 1.


Abbreviations:
ALH

atypical lobular hyperplasia

DCIS

ductal carcinoma in situ

ER

oestrogen receptor

IDC

invasive ductal carcinoma

ILC

invasive lobular carcinoma

LCIS

lobular carcinoma in situ

NHSBSP

National Health Service Breast Screening Programme

PLCIS

pleomorphic variant of lobular carcinoma in situ

PR

progesterone receptor

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical considerations
  5. The histopathology of lobular neoplasia
  6. Molecular pathology and cytogenetics
  7. Acknowledgements
  8. References

The historic view that lobular carcinomas emanate from the lobules and ductal carcinomas from the ducts was challenged long ago by the seminal studies of Wellings, which demonstrate that most breast cancers arise from the same locality, the terminal duct lobular unit.1 Many data now indicate that the differences that characterize breast cancer morphology are manifestations of their differing molecular profiles.2

The term lobular neoplasia defines a continuum of diseases,3 from risk indicators for malignant disease, e.g. atypical lobular hyperplasia (ALH), through to lesions that are fully malignant and can lead to death for the patient. An attempt to stratify this continuum on a logical morphological basis has been made with LIN terminology;4,5 however, this does not seem to have gained wide acceptance. Nevertheless, invasive lobular carcinoma (ILC) represents a relatively well-defined tumour both morphologically and genetically, particularly when compared with the diverse group of lesions which we classify as ‘ductal’ type cancers.2 Consequently, studies which seek to compare different aspects of the pathobiology of ILCs with invasive ductal NST [invasive ductal carcinoma (IDC)] can be difficult to interpret.6,7

The defining pathological features shared by classical examples of lobular lesions are populations of small aberrant cells with small nuclei, individual ‘private’ acini and a lack of cohesion between cells. Lobular neoplasia is also associated with a number of distinctive biological characteristics, including an increased risk of bilateral disease and, for ILC, multifocality with ‘skip’ lesions, an increased propensity for transcoelomic metastases and spread to unusual sites, of which components of the gastrointestinal tract appear the commonest locations.8–11 In this article we will review some of the clinical features of lobular neoplasms, the histopathology and molecular pathology of the different subtypes and the practical relevance of these divisions. Space constraints do not allow this to be an exhaustive review – rather it is a selective one.

Clinical considerations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical considerations
  5. The histopathology of lobular neoplasia
  6. Molecular pathology and cytogenetics
  7. Acknowledgements
  8. References

The epidemiology of lobular carcinoma is of interest. Unlike ductal carcinomas, lobular carcinomas, as a group, have continued to rise in incidence, most notably in women aged ≥50 years; increased mammographic screening alone is unlikely to be responsible for the observed rise in ILC.12 In the main, epidemiological factors acting on ILC, rather than breast cancer generally, remain unknown. One potential factor is alcohol; a recent study has found that alcohol use is related to a statistically significant risk of ILC, but not other breast cancer types, although the relatively low numbers involved draw from the authors a note of caution concerning this conclusion.13

There is an increased long-term risk of subsequent invasive carcinoma after a diagnosis of in situ lobular neoplasia, but, despite this, and because of the prolonged time for this to occur on average, the in situ lobular neoplasia spectrum is treated as a risk lesion for management purposes (reviewed in depth14). Some have recently challenged this view and proposed more active treatment in certain populations.15 However, the risk differs between ALH (4–5× risk) and lobular carcinoma in situ (LCIS; 8–10× risk), and some have reasonably proposed that these ends of the spectrum are delineated for purposes of risk stratification, with more active treatment being appropriate in certain populations.14 One of the characteristic features of in situ lobular neoplasia is its propensity to exist in multiple foci within either the same or both breasts;16–18 >50% of patients may have LCIS in the opposite breast. However, although the risk of malignancy applies to both breasts, the risk appears greater in the ipsilateral than contralateral breast.19,20 The literature also documents a high rate of bilaterality for ILC. Arpino has documented the clinical and biological features of 4140 patients with ILC compared with 45 169 patients with IDC; contralaterality was clearly higher for ILC patients than for IDC patients (20.9% versus 11.2%; P < 0.0001).21 These data support the view that some patients have an underlying genetic propensity to develop these types of tumours. It is interesting to speculate whether this genetic predisposition may also apply to low-grade ductal carcinoma in situ (DCIS) and grade 1 ductal carcinoma, given the basic cytogenetic similarity between some low-grade ductal carcinomas and lobular carcinomas (see below). However, as yet, no large studies have looked at bilaterality in ductal neoplasia segregated according to grade.

With the exception of rarer forms of LCIS with necrosis and associated microcalcification, typically the pleomorphic variant (PLCIS), in situ lobular neoplasia is in general radiologically covert. ILCs are also typically harder to detect than other types of invasive breast cancer,18 and ultrasound and mammography cannot detect all of them. In one study, re-examination of 46% of a series of mammograms that were false negative on initial interpretation still showed no evidence of malignant tumour on review.22 Size estimation of these tumours is also less reliable.23,24 Furthermore, it should be noted that there are no mammographic differences of practical use able to distinguish reliably between ILC and IDC.25,26 Overall, magnetic resonance imaging seems to be most sensitive imaging technique for detection of ILCs.24,27–29

Overall, in terms of patient survival, ILC and IDC appear broadly similar: 5-year overall survival rates of 85.6% for ILC and 84.1% for IDC (P = 0.64) have been demonstrated.21 A marginal difference in 5-year disease-free survival has been reported in the same study (85.7% for ILC versus 83.5% for IDC; P = 0.13),21 but given the diversity of biologies encompassed in the subgroups of both ILC and IDC and the prolonged biology of breast cancers in general, these data may be of only limited value.

The histopathology of lobular neoplasia

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical considerations
  5. The histopathology of lobular neoplasia
  6. Molecular pathology and cytogenetics
  7. Acknowledgements
  8. References

ALH and LCIS: in situ lobular neoplasia

Traditionally, non-invasive ‘lobular’ proliferations are divided into ALH and LCIS. In ALH a terminal duct lobular unit is partly or wholly colonized by small discohesive cells whose cytoplasm may contain variably conspicuous ‘private’ acini. The colonized units are not expanded and their lumina are not obliterated by this proliferation. In general, this proliferation is not widespread and does not extend in an undermining fashion into ducts as pagetoid spread (Figure 1). Conversely, LCIS is comprised of a population of cells with similar cytomorphological characteristics, but the colonized structures are expanded and the lumina lost. Although, as indicated above, there is an increased risk of associated invasion in LCIS compared with ALH, the morphological distinction between these lesions can be blurred. They also have a shared cytogenetic and molecular profile and the lesions often coexist. A plausible view is that they represent points on a temporal continuum, with LCIS evolving from ALH. Therefore, the terms lobular neoplasia30 or, more recently, in situ lobular neoplasia to encompass both lesions are practical developments that overcome the subjective nature of the division. Evidence is also accumulating that flat epithelial atypia/columnar cell change is also related and forms part of an evolutionary chain culminating in lobular neoplasia31,32 and also part of a complex with low-grade ductal neoplasia32 (see also cytogenetic considerations, discussed below).

image

Figure 1.  Pagetoid spread involves the neoplastic cells growing underneath, or between, native epithelial cells. In this case the undermining lobular carcinoma in situ cells are growing beneath the cells of low-grade flat and micropapillary ductal carcinoma in situ. This phenomenon can also be seen in association with flat epithelial atypia (FEA) and columnar cell change. All these lesions share a broadly similar cytogenetic profile.

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The cytological similarities between lobular neoplasia in situ and ILC suggest that the temporal continuum extends to invasive disease,33 although the certainty and time course of progression to invasion vary greatly between individual cases. This view is supported by cytogenetic evidence (see below). In addition, both ALH and LCIS frequently resemble typical ILC with respect to expression of molecular markers, being oestrogen receptor (ER) and progesterone receptor (PR) positive, and HER2 and p53 negative.34–36

Morphological variants of LCIS, such as ILC, can be identified. The most thought provoking of these is PLCIS, although it is worth noting that with regard to the variants of ILC also detailed below, the accompanying LCIS typically shares cytological characteristics.

Pleomorphic lobular carcinoma in situ

This entity has become increasingly recognized. Overall, the general characteristics are those of LCIS, but the nuclei are more pleomorphic, typically scoring 3 if the nuclear grading criteria embedded in the modified Bloom and Richardson criteria are applied37,38 (Figure 2). Nucleoli are more obvious in some examples. These lesions are more likely to be associated with comedo-type necrosis and microcalcification, and consequently their apparent increased incidence may be partly due to the effective detection of calcified lesions at mammographic screening. A further factor may be better recognition and classification by pathologists. As well as sharing cytological features both with invasive pleomorphic lobular carcinoma and some high-grade ductal neoplasms, the immunophenotype can also be similar. Thus, PLCIS is often ER− and PR− and HER2+. Additionally, a raised Ki67 index and increased gross cystic disease fluid protein 15 and p53 immunoreactivity can also be demonstrated.5

image

Figure 2.  Ducts, or perhaps more probably in this case lobules, expanded by pleomorphic lobular carcinoma in situ showing central comedo-type necrosis with calcification. This type of in situ lobular neoplasia can be revealed by mammography, unlike most in situ lobular neoplasia.

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As discussed above, LCIS is regarded as a risk indicator for the subsequent development of invasive carcinoma, which may develop in either breast after a prolonged period of time, or not at all. This view, which forms the basis for the B3 categorization of LCIS in cores as recommended by the National Health Service Breast Screening Programme (NHSBSP), has developed largely around studies of all LCIS. Naturally, there is some disquiet about this conservative treatment of PLCIS, since these lesions have molecular profiles that imply high-grade biology. Data are accruing to support a more aggressive treatment approach for PLCIS. However, evidence has not reached levels leading to universal acceptance of this strategy. Nevertheless, PLCIS often has a morphology resembling high-grade DCIS and, where there is doubt, reporting such cases as mixed PLCIS/DCIS seems prudent.

Invasive lobular carcinoma morphological diversity and variants

ILC represents up to 14% of all invasive breast cancers.39 A number of morphologically distinct ILC subtypes are commonly accepted, and it is worth noting that there remains great diversity in morphology even within the majority ‘classic’ subtype; for example, although the majority of these tumours grade as 2, some grade as 1. This variation suggests that further subtyping of ILC may be useful through integrated clinical, morphological, cytogenetic and molecular studies to inform the taxonomy.

In many texts the established subtypes of ILC are given as solid, alveolar, pleomorphic and tubulo-lobular. These types may exist with each other or with non-variant disease, and in these circumstances the NHSBSP Pathology Co-ordinating Group has proposed the term lobular mixed type.38 As a group, the variant lesions have a worse prognosis than the classic form.40 For these variants, in our experience, mixed patterns are commonplace, in particular for both solid and alveolar subtypes; a pleomorphic element is often seen.

Classic subtype

As originally defined, cells within these tumours have distinctive small nuclei, sometimes described as ‘lens-like’,40 as a consequence of indentation by small mucin-filled private acini, which are a classic feature of these lesions. These private acini can be variable in size; in many tumours they are inconspicuous and revealed by mucin stains, whereas in some they are striking and give the tumour a classical signet-ring cell morphology. Nucleoli are usually not visible. Mitoses are rare to sparse in most cases. The growth pattern is distinctive, with linear arrangements of cells running between collagen fascicles forming so-called ‘Indian files’. These arrangements often orientate themselves around fixed structures such as ducts in a whorled ‘targetoid’ manner.41,42 Skip lesions, where patches of tumour are seen separated from the main lesion by uninvolved breast tissue, are often seen. The overall cytogenetic profile of these lesions resembles that of grade 1 ductal carcinoma.43,44

Pleomorphic subtype

This subtype displays marked nuclear pleomorphism with nuclei scoring 3 according to the modified Scarfe, Bloom and Richardson grading system, as described by Elston and Ellis37,38 (Figure 3). The tumours have a more aggressive biology, more commonly grade as 3, and generally have a higher mitotic index. The growth pattern is as classic pattern lobular carcinoma in many cases. However, the architecture may be more mixed, and pleomorphic nuclei often feature within the regions of alveolar or solid subtypes. The immunohistochemical profile can differ markedly from classic pattern lobular carcinoma, with HER2 overexpression, immunodemonstrable p53 and, in some cases, loss of expression of ER and PR.45,46 Increased expression of high-molecular-weight cytokeratins and chromogranin has been noted.37 The HER2 overexpression is associated with amplification of the gene locus on 17q. Other cytogenetic changes, as revealed by comparative genomic hybridization, are more widespread than those in classic pattern ILC, and therefore the cytogenetic profile more resembles grade 3 ductal carcinomas, than grade 1 ductal carcinomas, as with the rest of the subtypes of lobular carcinoma.

image

Figure 3.  Invasive lobular carcinoma (ILC), pleomorphic variant. The general characteristics of discohesion and Indian file formation can be appreciated here, but, unlike conventional-type ILC, the nuclei show high-grade pleomorphism. This variant of ILC may be oestrogen receptor and progesterone receptor negative and HER2 positive, unlike most lobular carcinomas.

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Apocrine/histiocytoid subtypes

Cells within these tumours often have large, overtly nucleolated nuclei and copious cytoplasm; the overall cytomorphology may resemble macrophages – hence the term ‘histiocytoid’47 (Figure 4).

image

Figure 4.  Invasive lobular carcinoma (ILC), pleomorphic variant. This lower power image shows the large size of the tumour nuclei in comparison with adjacent lymphocytes. It also shows the brisk lymphocytic infiltrate that may occasionally be seen in ILC. This phenomenon may resemble a classic lymphocytic lobulitis and, on occasion, obscure the malignant population.

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Alveolar subtype

This distinctive pattern forms rounded aggregates of invasive neoplastic cells in a manner that mimics LCIS, but lacking the encompassing myoepithelial/basal cells and basement membrane. This pattern often forms a subset in a mixed growth pattern.

  • image(5)

[  Invasive lobular carcinoma apocrine/histiocytoid variant. Here the tumour cells are present in the tissue surrounding a terminal duct. The neoplastic population is characterized by generous amounts of pink cytoplasm on H&E and can bear more than a passing resemblance to histiocytes. Such a tumour could be overlooked on casual inspection. ]

  • image(6)

[  Invasive lobular carcinoma alveolar variant. The neoplastic population of discohesive cells forms rounded aggregates which produce a superficially similar picture to an area of lobular carcinoma in situ, but clearly are not encompassed by a basement membrane. ]

Solid subtype

In this variant, the neoplastic cells form sheets and, as such, can mimic other lesions, most notably lymphoma. Commonly, the lesion possesses high-grade nuclei. Close examination often reveals areas of classic Indian filing, usually at the margins of the lesion, although it should be noted that lymphomas can also show this cellular arrangement.

Tubulo-lobular subtype – not really a lobular carcinoma at all

First described by Fisher in 1977,48 this tumour is characterized by the overall cytological features of classic ILC, including Indian files and targetoid configurations, but differs on account of the presence of small-calibre tubules. It is important to note that the lesion is not the same as a mixture of tubular and infiltrating lobular carcinoma, for which the terminology tubular/lobular mixed should be applied. However, other authors imply that it is a lesion more like tubular carcinoma than lobular.49

Although initially felt to have a prognosis part way between tubular and lobular carcinoma,48 recent evidence has shown such lesions to have the best prognosis of all breast cancer subtypes,50–52 with one study showing a 10-year survival of 91%, narrowly ahead of tubular carcinoma at 90%. By comparison, the figures for grades 1 and 2 lobular carcinoma were 71% and 55%, respectively.51

In recent years the inclusion of this lesion in the lobular carcinoma family has been considerably undermined. Using a three-dimensional modelling system to compare 22 tubular and 20 tubulo-lobular carcinomas, Marchio et al. have shown that both contained a mixture of cords of cells with tear drop-like blebs forming a necklace-like structure. Tubulo-lobular lesions showed a much higher degree of crowding and architectural complexity, and the apparent cords of cells were revealed as walls of cells rather than files.49 Several studies have shown most tubulo-lobular carcinomas to be positive for E-cadherin and have concluded that this tumour is more akin to ductal carcinoma than a ‘proper invasive lobular carcinoma’.4,49,52 Although one study has shown a small subset of tubulo-lobular carcinomas to be negative for E-cadherin, unlike ILC, these cases were positive for either α- or β-catenin.52 The observation that tubulo-lobular carcinoma is commonly accompanied by LCIS has led some authors to conclude that lesions are truly lobular/ductal carcinoma hybrids52– not surprising in view of the cytogenetic similarity between low-grade ductal and lobular carcinomas;43,44,53 however, overall these lesions seem better categorized with ductal-type carcinomas.

Molecular pathology and cytogenetics

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical considerations
  5. The histopathology of lobular neoplasia
  6. Molecular pathology and cytogenetics
  7. Acknowledgements
  8. References

The hallmark molecular feature of lobular malignancies, of both in situ and invasive forms, is loss or down-regulation of E-cadherin (CDH1).54–62 This is manifest in routine practice by immunonegativity for the molecule E-cadherin, an adhesion molecule localized at the zonula adherens of epithelial cells which enhances cellular cohesion by homotypic interactions.63–65 Loss of expression occurs by a combination of loss of heterozygosity, gene mutation or promoter silencing leading to biallelic inactivation of the gene.54,55,57–59,66 The cytoplasmic domain of E-cadherin interacts with the catenins, β and γ (also known as plakoglobin), which in turn are able to communicate with the actin cytoskeleton via α-catenin. Furthermore, γ- and β-catenin, which compete with each other,67 are, under some circumstances, able to act as transcription factors.68 Transcriptionally active β-catenin in a nuclear localization is able to up-regulate c-myc and cyclin D1.69,70 As a consequence, loss of E-cadherin may have ramifications for cell adhesion, motility and possibly cell division. The loss of demonstrable E-cadherin has led to some reliance being placed on E-cadherin negativity as a diagnostic feature of lobular carcinomas. However, caution should be exercised in using this as a definitive test, since ductal carcinomas can also be E-cadherin-negative, either wholly or partly, and yet still show clear ductal morphology.71 E-cadherin expression within these ductal carcinomas is likely to have been down-regulated to below detectable levels rather than formally lost, and this may be accompanied by compensatory up-regulation of other members of the cadherin family, such as H-, P- or N-cadherin. Therefore, E-cadherin immunopositivity must be interpreted carefully, taking into account the overall morphological context.

The rest of the molecular profile of classic lobular neoplasms is distinctive, although not entirely unique. They are typically epidermal growth factor receptor 1 and HER2-negative, and the antibody 34bE12 (cytokeratins 1, 5, 10 and 14),4,5 ER and PR positive.21 It should be noted, however, that some ductal carcinomas share this profile71,72 and that pleomorphic lobular carcinomas can be ER−, PR− and HER2+ (and HER2 gene amplified).46

Cytogenetic studies have shown that classic lobular carcinomas have relatively low numbers of changes compared with pan-grade cohorts of breast cancers. The classic changes are loss of 16q and gain of 1p and, in this regard and in terms of overall numbers of changes, lobular carcinomas resemble grade 1 ductal carcinomas.43,73 This cytogenetic similarity, and the fact that mixed ductal grade 1/lobular tumours are relatively common, has led to the conclusion that these lesions are closely related.74 The morphological difference from ductal carcinoma is due to biallelic inactivation of the E-cadherin gene and consequent profound morphological alterations, in comparison with grade 1 ductal carcinomas, where one allele is retained. The cytogenetic profiles of variant pattern lobular carcinomas have been most documented in pleomorphic lobular carcinomas. In a study of one example of pleomorphic ILC, there were more changes than in conventional lobular carcinomas, notably including amplification of c-myc and HER2. There were not, however, as many changes as seen in ductal cancers, and these changes, qualitatively, still resembled ILC more than high-grade IDC.75

More recent studies have suggested that there are a number of other specific and distinctive molecular changes seen in lobular carcinomas, most notably amplification of the fibroblast growth factor receptor 1 (FGFR1) gene at a complex locus 8p11.2.76 This change is not wholly lobular specific as it occurs in other low-grade breast tumours, typically those that are ER+.77 This amplification identifies the receptor as a novel, potential therapeutic target.76

Interestingly, some rare families have been detected whose kindred have a heritable defect in the E-cadherin gene and who develop either lobular carcinoma or diffuse gastric carcinoma, or both.78

In summary, lobular carcinoma is a diverse group of diseases presenting a challenge to the cancer biologist to identify the molecular basis of the heterogeneity, to the pathologist to assess correctly the wide range of morphologies, and to the clinician to manage the diseases in the context of greatly differing biologies. The morphological and cytogenetic diversity implies a spectrum of neoplasms unified by the common features of loss of E-cadherin function and a close relationship to low-grade ductal carcinoma. Distinct issues remain to be resolved, notably the risk associated with PLCIS and the genetic basis of the frequent bilaterality.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical considerations
  5. The histopathology of lobular neoplasia
  6. Molecular pathology and cytogenetics
  7. Acknowledgements
  8. References

AMH and TAH are supported by the Breast Cancer Research Action Group (UK Charity No. 1075308), the Breast Cancer Campaign (UK Charity No. 5074725), and Yorkshire Cancer Research (UK Charity No. 516898).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical considerations
  5. The histopathology of lobular neoplasia
  6. Molecular pathology and cytogenetics
  7. Acknowledgements
  8. References
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