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Fibroepithelial neoplasms of the breast
PATHOLOGY OF BENIGN BREAST DISEASE
Fibroepithelial neoplasms of the breast
hides the fact that there a number of unclear areas. For some categories these considerations may not be important; for example, whether lactating adenoma is an entity in its own right or a fibroadenoma with superimposed lactational change. For others these considerations are more significant; phyllodes tumours include some lesions that recur and some lesions that are malignant.
Andrew M Hanby Rebecca Millican-Slater Benjamin Dessauvagie
Fibroadenoma e conventional type These are harmless lesions and if tissue diagnosis is made, typically by core biopsy, there is an increasing tendency for them to be left and not excised, although continued growth and/or late presentation may prompt surgery. Fibroadenomas are well-defined lesions which may be multiple in up to 20% of cases. They are clearly delineated from the surrounding breast and, as a consequence, can be quite mobile within the breast, hence the term ‘breast mice’ is sometimes used. There is a great variation in size. Typically they are firm and rubbery, but can be hard on the rare occasion when there is internal calcification. Often they have a bosselated gross appearance and have a white cut surface, with clefting sometimes discernible on macroscopic examination. As indicated above these tumours represent co-proliferations of epithelium and stroma with both elements growing in concert. Traditionally, intracanalicular variants, with the epithelium arranged in clefts, and pericanalicular variants, where the epithelium is arranged in rounded acini-like configurations, are identified, although elements of both can commonly be seen in the same lesion (Figure 1). Stroma is of uniform cellular density which varies from almost acellular in long-standing, hyaline variants, to highly cellular in so e called ‘cellular fibroadenoma’. Neither the intracanalicular nor the pericanalicular pattern has any particular clinical connotation, although since the former is also seen in phyllodes tumours, intracanalicular fibroadenomas are those most likely to cause diagnostic difficulty.
Abstract Fibroepithelial neoplasms include a large number of common lesions encountered in both symptomatic and breast screening practice. Nearly all are fibroadenomas and are harmless, but they can present a range of differing histologies. The area of most concern is the separation of fibroadenomas from phyllodes tumours, arguably an arbitrary exercise at the benign end of the spectrum. What is most important to achieve is the recognition of those lesions in the fibroadenoma-phyllodes spectrum with the potential to do harm, either in the form of recurrence or metastases. These are few in number and the key features to identify, with the rare exception of carcinoma arising in these lesions, are those that signify a progression to stromal autonomy. Such features include stromal overgrowth, stromal invasion, stromal cell atypia and stromal mitotic activity. These need to be analysed together, not in isolation. Necrosis and heterotypic elements in particular are suggestive of frank malignancy.
Keywords fibroadenoma; hamartoma; lactating adenoma; phyllodes tumour; tubular adenoma
Introduction This review is concerned with neoplasms characterized by a coproliferation of epithelium and stroma. Under this heading come a number of benign lesions such as lactating adenoma, tubular adenoma, fibroadenoma and the low grade end of the phyllodes tumour spectrum. At the other end of the spectrum are borderline and malignant phyllodes tumours. For some malignant phyllodes tumours only a sparse residual epithelial component may remain. The classifications of these lesions are morphology based and in many cases the comfort zone provided by pigeonholing entities into specified nomenclature
Fibroadenoma e epithelial proliferations Fibroadenomas may show a number of epithelial phenomena superimposed on their basic architecture; for example, usual ductal hyperplasia, sclerosing adenosis, squamous metaplasia and lactational change. ‘Complex fibroadenoma’ is recognised where there is one or more of the following features: papillary apocrine hyperplasia, cysts over 3 mm in size and epithelial calcifications (Figure 2).1 Up to 16% of fibroadenomas fall into this category.2 Recent large population studies have indicated that the long held belief of a modest increase in malignancy following a diagnosis of complex fibroadenoma,2 is actually due its frequent associated with other, well established risk factors such as proliferative breast disease and not the complex fibroadenoma itself.3 Fibroepithelial neoplasms and particularly phyllodes tumours are more prone to containing coexisting carcinoma, of which in-situ malignancy is most common; in situ ductal and lobular carcinoma have both been described at relatively equal frequency.4 Invasive carcinoma is less common and, where this is detected, it is important to ascertain whether it is wholly confined to the dominant lesion or has extended into it from the rest of the breast.
Andrew M Hanby FRCPath is a Professor of Pathology at the Leeds Institute of Molecular Medicine, and the Yorkshire Cancer Research & Liz Dawn Pathology and Translational Sciences Centre, St James’s University Hospital, Leeds, UK. Conflicting interests: none. Rebecca Millican-Slater FRCPath is a Consultant Pathologist at Leeds Teaching Hospitals NHS Trust, Leeds, UK. Conflicting interests: none. Benjamin Dessauvagie FRCPA is a Consultant Anatomical Pathologist at PathWest Laboratory Medicine, Fiona Stanley Hospital, Western Australia, Australia and an Adjunct Senior Lecturer in the School of Pathology and Laboratory Medicine at the University of Western Australia. Conflicting interests: none.
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Please cite this article in press as: Hanby AM, et al., Fibroepithelial neoplasms of the breast, Diagnostic Histopathology (2017), http://dx.doi.org/ 10.1016/j.mpdhp.2017.03.012
PATHOLOGY OF BENIGN BREAST DISEASE
Figure 3 Myxoid fibroadenoma. A fibroepithelial neoplasm with a sharp interface with adjacent fat. The stroma is distinctly loose, mucoid and relatively acellular, and grossly the cut surface of the lesion is glistening with an almost translucent look. Figure 1 Fibroadenoma. Example of a typical, mostly intracanalicular pattern, fibroadenoma in core biopsies. The cores show no fragmentation and are mostly comprised of a co-proliferation of epithelium and stroma, the latter forming a sharp interface with adjacent fat. The stromal cellularity is low and there is no obvious condensation of stromal nuclei.
Figure 4 Pattern of mucoid change sometimes seen in primary pigmented adrenocortical disease (Carney complex). Here scattered mucoid change is seen in the breast, not specifically forming a distinct ‘adenoma’. It is not known if this example was a proven Carney complex case.
myxomas, cutaneous myxomas, spotty pigmentation and endocrine hyperactivity and is associated with abnormalities in the PRKAR1A gene.5 In one case known to the authors, the diagnosis of the breast lesion pre-dated identification of a left atrial myxoma. In lesions associated with this syndrome, the stroma is extremely loose. Indeed, such loose myxoid change can be seen within the breast stroma divorced from any defined lesion with characteristics of a fibroadenoma6 (Figure 4) and this change may be more obvious in the inter- rather than intra-lobular stroma. It should be noted that most myxoid fibroadenomas are not associated with Carney complex and do not have any harmful associated conditions.
Figure 2 Complex fibroadenoma. Core biopsy showing early sclerosing adenosis and apocrine metaplasia with cyst formation and occasional calcifications.
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Fibroadenomas exhibit varied, sometimes worrying appearances, due to diverse benign stromal and epithelial changes Carcinoma may rarely occur in fibroadenomas
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Fibroadenoma e myxoid Some fibroadenomas have a very loose myxoid matrix with a glistening cut surface (Figure 3). Lesions of this type have been associated with the rare Carney complex, which includes cardiac
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Myxoid fibroadenomas may, rarely, be associated with other systemic abnormalities as part of Carney complex
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PATHOLOGY OF BENIGN BREAST DISEASE
may show infarction and this can be extensive (Figure 6). Whilst in some lesions the vestige of a fibroadenoma or tubular adenoma can suggest a derivation from it, in other cases it is less clear that this lesion is a tumour and instead represents merely a dominant lactating lobe.9 These lesions are important in so much as they may present as a hard mass during pregnancy and therefore raise concern. Their diagnosis is usually straightforward and, of themselves, have no serious clinical implications.
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Figure 5 Stromal giant cells. Such cells may be seen in a variety of fibroepithelial neoplasm and are sometimes numerous. This example is within a borderline phyllodes tumour. Such cells do not carry any specific behavioural connotations.
Tubular adenoma As originally described, these tumours comprise closely packed tubules with little intervening stroma and, in some examples, prominent lymphocytes. Observation of the practice of fellow pathologists suggests that there is diagnostic terminological drift to include lesions where the glands may not be so well packed and stroma more evident (Figure 7). Additionally, lesions with hybrid fibroadenoma features are also seen.9 In any event, these lesions have no harmful implications.
Fibroadenomas with multinucleated stromal giant cells On occasion an otherwise typical fibroadenoma may contain bizarre, pleomorphic and/or hyperchromatic fibroblasts7,8 (Figure 5). These may be plentiful and unnerving to the unwary. Crucially these rarely have associated stromal mitoses. They may also be seen in phyllodes tumours.7 Such fibroblasts are not associated with any behavioural significance in either fibroadenomas or phyllodes tumours.
Juvenile fibroadenoma The presentation of these lesions may be alarming with rapid growth and distortion of the breast sometimes seen.10 Such a presentation combined with what can be a very striking histological picture may suggest a phyllodes tumour (see below) to the unwary. Grossly juvenile fibroadenomas are well-defined and encapsulated masses. Microscopically, mitotic activity and stromal cellularity may be very marked. Unlike phyllodes tumour,
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‘Lactating’ adenomas may infarct
Giant cells in fibroepithelial neoplasms are generally of no significance
Lactational/lactating adenoma As might be expected, these lesions occur during pregnancy and during lactation. They may be quite large and biopsies reveal a mass of closely packed lactating acini/glands On occasion these
Figure 7 ‘Tubular adenoma’. A lesion which many pathologists would now call a tubular adenoma being comprised largely of tubular components. An excess of lymphocytes is seen and is a common accompaniment of these lesions. It is important to note that lesions like the one illustrated here do not fulfil the criteria for tubular adenoma as originally described, since classic examples should show little or no surrounding fibrous stroma and often have very inconspicuous myoepithelium. Perfect examples are, in this author’s experience, very rare.
Figure 6 Lactating adenoma. Core biopsy showing infarction with a peripheral subcapsular rim of viable adenomatous tissue.
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PATHOLOGY OF BENIGN BREAST DISEASE
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Figure 9 Myoid differentiation in a fibroadenoma. This fibroadenoma shows both sclerosing adenosis towards the top and clear myoid differentiation (towards the middle and bottom of the core). If there is any doubt the lesion can be stained for markers to desmin which will illuminate the slips of smooth muscle. Such a change may be focal or extensive throughout the lesion, in which case the label myoid hamartoma can be used, although this does not carry with it any specific behavioural associations.
Myoid hamartomas/fibroadenomas with myoid differentiation Some benign fibroepithelial neoplasms show smooth muscle differentiation within the stroma, which may on occasion be striking but more often can be seen as a localized change. The smooth muscle cells will, as elsewhere, label with both smooth muscle actin and myosin. Such differentiation is not, of itself, associated with any particular biology, but where prominent may produce an unexpected appearance. Whilst some have related these lesions to mammary hamartomas (see below),13 in the authors’ experience others look more like fibroadenomas with extensive myoid differentiation (Figure 9).
b Juvenile fibroadenoma.a Stromal expansion and hypercellularity. b Detail of this illustrating gynaecomastoid epithelial hyperplasia in addition to stromal (A) and epithelial (B) mitoses (also insets). Figure 8 Juvenile fibroadenoma. (a) Stromal expansion and hypercellularity. (b) Detail of this illustrating gynaecomastoid epithelial hyperplasia in addition to stromal (A) and epithelial (B) mitoses (also insets).
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however, in juvenile fibroadenoma diffuse stromal cell atypia is absent, there is no relative stromal overgrowth, a pericanalicular architecture is seen and increased mitotic activity in the stroma (which can number up to seven per 10 high power fields (10 HPFs)) is matched by that seen in the epithelium (Figure 8). Often the epithelium may show a distinct pattern of epithelial proliferation whereby the hyperplasia resembles that seen in gynaecomastia.11 This ‘gynaecomastoid hyperplasia’ is distinctive of these lesions. In some rare cases atypical epithelial proliferations are seen.12 The clinical outcome of juvenile fibroadenoma is no different to conventional fibroadenoma.10
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Mammary hamartoma and pseudoangiomatous stromal hyperplasia Whether mammary hamartoma qualifies as a fibroepithelial neoplasm is debatable. Certainly these enigmatic lesions do not fit the dictionary description of a ‘hamartoma’. They warrant a place in this review as they are lesions that manifest as welldefined breast masses which clinically and radiologically can resemble fibroadenomas. On excision they are also well defined, typically with a white cut surface. In the authors’ experience they are more rubbery and softer than classic fibroepithelial lesions and are more compressible. These lesions typically contain the constituents of normal/benign breast tissue and a core biopsy may not present a distinctive picture from the rest of the breast.
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Juvenile fibroadenomas show both stromal and epithelial hyperplasia The hyperplasia is typically florid and resembles that seen in gynaecomastia e hence the term gynaecomastoid
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Smooth muscle differentiation may be seen in fibroepithelial neoplasm, some resemble fibroadenomas, others hamartomas
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PATHOLOGY OF BENIGN BREAST DISEASE
these examples often fall easily into one category or another, and are not the ‘grey’ examples seen in working practice with overlapping features that are open to subjective analysis. Perusal of the large amount of literature on phyllodes tumours and fibroadenomas reveals a range of appearances and biological features. This is matched by diversity in the number of different cut-offs devised by different groups and purporting to distinguish between the different categories. Some understanding of the known molecular, cytogenetic and cell biological features underlying these lesions can help to make some sense of what is going on and to make a judgement of the likely behaviour of such lesions. Benign fibroepithelial lesions represent a good illustration of the phenomenon of epithelial-stromal cross-talk. In benign lesions the stromal and epithelial elements grow in concert because they influence each other either through direct cell contact or secreted products, and most likely both. We know very little if anything about what initiates these lesions. In some examples of phyllodes tumours, loss of heterozygosity (LOH) studies show that abnormalities can exist in either the stroma or the epithelium,15 but this does not per se imply that they are causative. In both fibroadenomas and most phyllodes tumours, mRNA for the wnt molecules, 5a and two, can be detected; 5a in the epithelium and two in both the epithelium and stroma. The changes are more pronounced in the group classified as phyllodes than those classified as fibroadenoma using traditional criteria, but do not permit clear cut-offs between these groups. The wnts are able to influence a number of signalling pathways; for example, wnt2 can lead to upregulation of transcriptionally active b-catenin, which in turn is able to effect proliferation via upregulation of a variety of effectors of which cyclin D1 and cmyc are examples.16 This is what is seen in fibroadenomas and most phyllodes tumours, with b-catenin demonstrable in the stromal nuclei and also, most markedly in the phyllodes group, an increase in c-myc and cyclin D1. Furthermore, upregulation of insulin-like growth factor 1(IGF1) mRNA can be shown in the stromal components of these tumours, whilst one of its receptors, IGFR1, is expressed on the epithelial cells. This interaction could represent an alternate mechanism of nuclear b-catenin accumulation in some fibroepithelial neoplasms.17 These observations together show how each component in these lesions can sustain the other and that the molecular observations between most lesions we call phyllodes and those we call fibroadenomas are shared. The situation changes dramatically at the malignant phyllodes end of the spectrum. In these tumours the stromal element shows no nuclear b-catenin, the wnts are not upregulated and new abnormalities such as c-kit, PAX3, SIX1, HMGA2 and TGFB1 upregulation, c-myc and EGFR1 amplification, and p16INK4a inactivation can be demonstrated.18e20 Furthermore, there is more frequent LOH and increasing complex karyotypic changes.20,21 Such abnormalities reflect a stromal population no longer dependent on the epithelial crosstalk and now autonomous. In summary, when making individual decisions to fit a lesion into the conventional categories, it is important to realize that these categories are not set in stone, that their borders are blurred and that fibroadenomas and phyllodes tumours may form part of one spectrum, a difficulty reflected in other
Figure 10 Mammary hamartoma. Photomicrograph of a portion of a sample from a radiologically and clinically well-defined lesion. It shows very marked pseudoangiomatous hyperplasia (PASH), a phenomenon characterized by a collagenous stroma exhibiting marked clefting resembling the slit-like spaces seen in some vascular neoplasms. The histology of hamartomas is very variable and samples from lesions show a histology inseparable from normal breast tissue.
Only radiological proof of origin of the examined tissue from a well-defined mass permits diagnosis. However, the stroma is often distinctive and shows pseudoangiomatous stroma hyperplasia (PASH) (Figure 10). This is characterized by a rather sclerotic matrix containing slit-like spaces arranged in a manner resembling angiomatous blood vessels. Associated stromal cells are CD34 positive but do not mark with specific markers of vasculature and probably represent myofibroblasts.14 This change is sometimes seen as a localized isolated phenomenon. Some authorities regard PASH as a lesion in its own right and indeed many regard mammary hamartomas as PASH.
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Hamartomas are well-defined lesions without the typical architecture of fibroadenomas PASH is commonly seen in hamartomas PASH may be seen in isolation
Phyllodes tumours and the fibroadenoma e phyllodes tumour spectrum At the heart of most concerns about fibroepithelial lesions is their distinction from phyllodes tumours. Phyllodes tumours form a spectrum from benign, through borderline, to malignant. There is a greater propensity to recur and, less commonly, to metastasize away from the benign ‘end’ of this spectrum. These behavioural traits distinguish these lesions, in the main, from fibroadenomas and for this practical reason many standard texts separate fibroadenomas from phyllodes tumours as clearly defined entities. In reality most tumours defined as phyllodes tumour do not recur. Furthermore, while many texts give illustrative examples of these classic lesions and compare them to fibroadenomas,
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PATHOLOGY OF BENIGN BREAST DISEASE
publications.22,23 Understanding the biology will help in making realistic judgements based on morphology. What follows is a reiteration of standard convention governing these lesions.
frank pleomorphism (Figure 11) being more typical of malignant phyllodes tumours and affecting more of the neoplastic stromal cells. As noted above, bizarre giant cells may not per se be indicative of malignancy.7 Stromal mitoses Fibroadenoma versus benign phyllodes tumours: in general, mitoses are very rare in fibroadenomas and few in number in benign phyllodes tumour, and are not the most useful distinguishing feature. However, it should be remembered that mitotic activity within juvenile fibroadenomas may be very high, but is matched by epithelial mitotic activity which is equivalently high within the context of that lesion (see above).
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Morphological and molecular evidence does not indicate such clear differences between some fibroadenomas and phyllodes tumours as some texts imply In benign fibroepithelial neoplasms the stroma and epithelium show evidence of ‘cross-talk’ and co-proliferation Malignant phyllodes tumours develop stromal autonomy
Benign versus borderline versus malignant phyllodes Tumours: in this spectrum the number of mitoses increases from benign through to malignant phyllodes tumours. There is variety in the cut off point suggested between different groups and whilst many regard this as one of the most important features in the differentiation of these groups, it is difficult to define a clear consensus, not least because many of the papers do not, for example, take into account field size in the mitotic counting.28 In the most recent WHO guidelines mitotic activity is described as ‘usually few’ with a cut-off of <5 per 10 HPFs for benign, ‘usually frequent’ (5e9 per 10 HPFs) for borderline and ‘usually abundant’ (10 per 10 HPFs) for malignant tumours.25 It is worth noting that the mitotic activity and cellularity often go hand in hand and there may be regional variation, and thus careful examination of the whole lesion and adequate sampling should be factored into the analytical process.
General clinicopathological features of phyllodes tumours These lesions occur most commonly in the 40e50-year age group.24,25 Although some have noted a lower age incidence in Asian populations, for example 25e30 years in a study by Chua et al.,22 in a series of 453 cases from Singapore the mean age was 42 years,19 similar to ‘Western’ populations. Gross As expected, lesions at the benign end of the spectrum, where they merge with fibroadenomas, do not differ from fibroadenomas in appearance. With borderline and malignant lesions the boundaries with surrounding tissue are less clearly defined, correlating with the increasing propensity to an infiltrative growth pattern. Additionally, in frankly malignant lesions, more fleshy large tumours with softening and cavitation associated with necrosis are seen.
Stromal cellularity Fibroadenoma versus benign phyllodes tumours: in general, phyllodes tumours are more cellular than fibroadenomas. However, this analysis is subjective23 and some lesions that are fibroadenomas in every other way may have a cellular stroma (cellular fibroadenoma, see above). More important is the
Histology Like fibroadenomas, benign phyllodes tumours represent a coproliferation of stroma and epithelium growing in concert. Progressing along the spectrum through borderline to malignant there is a progression of histological features. These features are stromal-to-epithelial ratio, the interface between the lesion and surrounding breast tissue, stromal cellularity, stromal (and epithelial) mitotic activity, stromal cell atypia and whether there is stromal necrosis. The combinations of these features are many and therefore for individual cases, judgement more than dogma is required. In assessing a fibroepithelial neoplasm in this spectrum, it is important that sampling is thorough as the morphology and indeed the cytogenetic profile may be heterogeneous.26 The proposal that grading is based on the worst area, as long as it is equal to or exceeds 10% of the tumour, is a reasonable strategy.27 The effect of fixation on such features such as mitotic activity should also be considered. Stromal cell atypia Fibroadenoma versus benign phyllodes tumours: in general, the fibroblasts in both these circumstances are relatively bland and nuclear pleomorphism is rarely a criterion used to separate them.
Figure 11 Malignant phyllodes tumour. This sample from a core biopsy displays not only the cellular stromal condensation next to the epithelium seen in many phyllodes tumours, but also the increased stromal cellularity, nuclear hyperchromasia and pleomorphism that may be seen.
Benign versus borderline versus malignant phyllodes Tumours: with progression from benign to malignant there is an increase in nuclear pleomorphism, with hyperchromasia and
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PATHOLOGY OF BENIGN BREAST DISEASE
distribution of the cellularity. In typical phyllodes tumours enhanced stromal cellularity is seen immediately beneath the epithelial element (Figure 11) and can appear quite pronounced on low power examination. In some cases, however, the condensation may be more pronounced remote from the epithelium (Figure 12).
Benign versus borderline versus malignant phyllodes Tumours: Lesions along this spectrum show an increasing tendency towards having a blurred/infiltrative interface with adjacent breast tissue, with the stromal element extending out into these tissues (Figure 13). This may be focal and limited in borderline lesions through to overtly and widely invasive in malignant examples. Where there is apparent recurrence after a previous excision, the analysis may be particularly challenging as the fibroblasts associated with the repair changes may resemble neoplastic fibroblasts and confound analysis of excision margins.
Benign versus borderline versus malignant phyllodes Tumours: In general, from benign through to malignant there is an increase in stromal cellularity with malignant lesions often very highly cellular (see Figure 11). Stromal overgrowth Fibroadenoma versus benign phyllodes tumours: Typically, phyllodes tumours have a higher stromal-to-epithelial ratio than fibroadenoma. However, at the benign end of the spectrum this is very subjective, the ratio varies between different fibroadenomas and on this feature alone the entities merge.
Architecture This is partly a manifestation of the effects of the features additionally described in this section. Classic phyllodes tumours have an intracanalicular rather than a pericanalicular growth pattern, with clefting being a typical feature. This of itself does not make the diagnosis, but the scale of the clefting is larger and the clefts are often wider and occasionally cystic. This partly accounts for one of the archetypal features of these lesions: the leaf-like configurations of bulging stroma overlain by epithelium (Figure 14). Analysis of even this feature is subjective and the other attributes must be taken into account.
Benign versus borderline versus malignant phyllodes Tumours: As indicated above, in both fibroadenomas and phyllodes tumours there is cross-talk between the epithelium and stroma with growth of one affecting the other. As autonomy of the stromal element develops, this is lost. This is reflected in the histology with increasing stroma relative to epithelium evident in the progression from benign, through borderline to malignant. In the latter, extreme parts of the lesion may be purely stroma, referred to as stromal overgrowth and arbitrarily defined as the presence of epithelium-free microscopic fields, and/or take on the appearances of a malignant spindle cell neoplasm.
Frank malignancy and heterologous elements Despite the criteria discussed above, correlation with behaviour is not perfect, and while most patients will not experience problems, occasionally apparent low-grade tumours will recur.29 At the malignant end, as indicated above, phyllodes tumours can show a frankly sarcomatous pattern characterized by a mitotically active, pleomorphic, cellular and invasive growth of neoplastic stromal cells and areas of tumour-cell necrosis. Faced with a sarcomatous lesion from the breast, a diligent search for remnant phyllodes architecture is essential to differentiate a pure stromal tumour/sarcoma from a malignant phyllodes tumour.
Interface between the lesion and the normal breast tissue Fibroadenoma versus benign phyllodes tumours: Both these lesions nearly always show a sharp interface with clear definition from adjacent breast tissue, and this feature does not serve to distinguish them.
Figure 12 Borderline phyllodes tumour. This illustrates a phyllodes tumour in which cellular stromal condensation is seen remote from the epithelium with a more subtle increase in cellularity next to the epithelium. It is important to note that for lesions such as this, all factors need to be taken into account in the assignment to a category. The prominent epithelium is in this regard a reassuring feature.
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Figure 13 Malignant phyllodes tumour. This demonstrates an extensively invasive tumour. The likelihood is that the epithelium seen here represents adjacent breast epithelium rather than the original lesional epithelium. Note the propensity for the stroma to condense around the epithelium and a field such as this resembles the appearances of periductal stroma tumour.
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PATHOLOGY OF BENIGN BREAST DISEASE
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Core biopsy of fibroepithelial lesions The interpretation of a core biopsy containing a fibroepithelial neoplasm has important management consequences. Generally, where a lesion is considered to be a fibroadenoma, no further action is taken. However, for a lesion interpreted as a phyllodes tumour or suspicious for a phyllodes tumour, excision of the lesion with a surrounding margin of benign tissue is recommended practice; ‘shelling out’ of the lesion is inappropriate and more likely to lead to recurrence in phyllodes tumours. Because of sample size and the reduced ability to see the overall tumour architecture, the differential diagnosis between fibroadenoma and phyllodes tumour is more of a challenge on needle core biopsies. Additionally, the sample may not even be from the most diagnostic area, so a core from a large lesion may not be representative. Of potential use diagnostically, in addition to the traditional features described above such as stromal cellularity and mitoses, the phenomenon of biopsy fragmentation occurs more commonly in phyllodes tumours than in fibroadenomas.33,34
Figure 14 Benign phyllodes tumour. This illustrates the classic architecture of phyllodes tumours with an exaggerated intracanilicular growth pattern with bulging stroma pushing into the epithelial-lined slits creating the so-called leaf-like pattern. Some of these spaces may become cystic.
Immunohistochemistry of fibroepithelial lesions A great number of molecular markers have been proposed to assist in this distinction. The basic science behind the biology of phyllodes tumours, as detailed above, gives some clue as to markers that could be of use; for example, the observation that there is downregulation of nuclear b-catenin in malignant phyllodes tumours could be of practical benefit. However, loss of a marker is never as attractive as acquisition, as when faced with a negative result there is always doubt regarding whether a test has worked. Some advocate strongly the value of CD34 as a positive marker in phyllodes tumours but not in fibromatoses or spindle cell carcinomas, from which distinction sometimes has to be made.23 Broadly speaking, however, morphology remains the mainstay in assigning a tumour to its position in the fibroadenoma-phyllodes spectrum.
Figure 15 Malignant phyllodes tumour. Heterologous osseous focus. Elsewhere in this lesion chondrosarcomatous elements were also found.
Phyllodes tumours can show diverse and often extensive heterologous malignant elements, including osteo-, chondro- and liposarcomatous differentiation (Figure 15).30,31,32 Indeed, such heterologous elements and necrosis were the only features shown to be significant in predicting metastasis-free and overall survival in a series of 77 phyllodes tumours in a multivariate analysis.24 Metaplastic carcinoma is outside the scope of this chapter, except to say that in some examples the combination of malignant spindle cells and more obvious glandular elements may suggest a fibroepithelial neoplasm and heterologous elements may be present. One of the key clues is the co-existence of both malignant glandular and stroma elements and the immunohistochemical detection of epithelial differentiation. Useful markers that may be positive in this regard include CAM5.2, CK5, CK14 and p63.
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Classifying fibroepithelial lesions along the fibroadenomaphyllodes spectrum requires assessment of a number of features and often a judgement call Necrosis and heterologous elements are highly indicative of a malignant lesion Heterologous elements may be seen in some metaplastic carcinomas
Periductal stromal tumour Periductal stromal tumour is a rare condition probably related to phyllodes tumours. Grossly they may appear multinodular. Microscopically neoplastic stromal cells, similar in cytological characteristics to conventional phyllodes tumours, insinuate diffusely around and spread along open mammary ducts, forming variably cellular cuffs. There is absence of the typical phyllodes ‘leaf-like’ architecture. Stromal cell CD34 positivity is noted.23 Some variation in nomenclature has occurred in the literature; periductal stromal sarcoma has been used to denote a
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PATHOLOGY OF BENIGN BREAST DISEASE
locally aggressive lesion with three or more mitoses per HPF and stromal nuclear atypia while periductal stromal hyperplasia has been used to described a benign lesion with bland stroma and rare mitoses.35,36 A
15 Sawyer EJ, Hanby AM, Ellis P, et al. Molecular analysis of phyllodes tumors reveals distinct changes in the epithelial and stromal components. Am J Pathol 2000; 156: 1093e8. 16 Sawyer EJ, Hanby AM, Rowan A, et al. The Wnt pathway, epithelialstromal interactions, and malignant progression in phyllodes tumours. J Pathol 2002; 196: 437e44. 17 Sawyer EJ, Hanby AM, Poulsom R, et al. Beta-catenin abnormalities and associated insulin-like growth factor overexpression are important in phyllodes tumours and fibroadenomas of the breast. J Pathol 2003; 200: 627e32. 18 Sawyer EJ, Poulsom R, Hunt FT, et al. Malignant phyllodes tumours show stromal overexpression of c-myc and c-kit. J Pathol 2003; 200: 59e64. 19 Tse GM, Lui PC, Vong JS, et al. Increased epidermal growth factor receptor (EGFR) expression in malignant mammary phyllodes tumors. Breast Cancer Res Treat 2009; 114: 441e8. 20 Karim RZ, O’Toole SA, Scolyer RA, et al. Recent insights into the molecular pathogenesis of mammary phyllodes tumours. J Clin Pathol 2013 Jun; 66: 496e505. http://dx.doi.org/10.1136/jclinpath-2012-201082. Epub 2013 Feb 12. 21 Lv S, Niu Y, Wei L, Liu Q, Wang X, Chen Y. Chromosomal aberrations and genetic relations in benign, borderline and malignant phyllodes tumors of the breast: a comparative genomic hybridization study. Breast Cancer Res Treat 2008; 112: 411e8. 22 Chua CL, Thomas A, Ng BK. Cystosarcoma phyllodes e Asian variations. Aust N Z J Surg 1988; 58: 301e5. 23 Lee AH. Recent developments in the histological diagnosis of spindle cell carcinoma, fibromatosis and phyllodes tumour of the breast. Histopathology 2008; 52: 45e57. 24 Cohn-Cedermark G, Rutqvist LE, Rosendahl I, Silfversward C. Prognostic factors in cystosarcoma phyllodes. A clinicopathologic study of 77 patients. Cancer 1991; 68: 2017e22. 25 Lakhani SR, Ellis IO, Schnitt SJ, eds. Pathology and genetics of tumours of the breast. Lyon: IARC Press, 2012. 26 Jones A, Mitter R, Springall R, et al. A comprehensive genetic profile of phyllodes tumours of the breast detects important mutations, intra-tumoral genetic heterogeneity and new genetic changes on recurrence. J Pathol 2008; 214: 533e44. 27 Moffat CJ, Pinder SE, Dixon AR, Elston CW, Blamey RW, Ellis IO. Phyllodes tumours of the breast: a clinicopathological review of thirty-two cases. Histopathology 1995; 27: 205e18. 28 Millis RR, Hanby AM, Oberman HA. The breast. In: Sternberg SS, ed. Diagnostic surgical pathology, vol. 1. New York: Raven Press, 1999; 319e85. 29 Rowell MD, Perry RR, Hsiu JG, Barranco SC. Phyllodes tumors. Am J Surg 1993; 165: 376e9. 30 Kefeli M, Yildiz L, Akpolat I, Balci P, Ozen N. The coexistence of invasive ductal carcinoma and malignant phyllodes tumor with liposarcomatous and chondrosarcomatous differentiation in the same breast in a post-osteosarcoma case. Pathol Res Pract 2008; 204: 919e23. 31 Norris HJ, Taylor HB. Relationship of histologic features to behavior of cystosarcoma phyllodes. Analysis of ninety-four cases. Cancer 1967; 20: 2090e9.
REFERENCES 1 Dupont WD, Page DL, Parl FF, et al. Long-term risk of breast cancer in women with fibroadenoma. N Engl J Med 1994; 331: 10e5. 2 Sklair-Levy M, Sella T, Alweiss T, Craciun I, Libson E, Mally B. Incidence and management of complex fibroadenomas. AJR Am J Roentgenol 2008; 190: 214e8. 3 Nassar A, Visscher DW, Degnim AC, et al. Complex fibroadenoma and breast cancer risk: a Mayo clinic benign breast disease cohort study. Breast Cancer Res Treat 2015 Sep; 153: 397e405. http://dx.doi.org/10.1007/s10549-015-3535-8. Epub 2015 Aug 12. 4 NM1 Diaz, Palmer JO, McDivitt RW. Carcinoma arising within fibroadenomas of the breast. A clinicopathologic study of 105 patients. Am J Clin Pathol 1991 May; 95: 614e22. 5 Groussin L, Kirschner LS, Vincent-Dejean C, et al. Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. Am J Hum Genet 2002; 71: 1433e42. 6 Carney JA, Toorkey BC. Myxoid fibroadenoma and allied conditions (myxomatosis) of the breast. A heritable disorder with special associations including cardiac and cutaneous myxomas. Am J Surg Pathol 1991; 15: 713e21. 7 Powell CM, Cranor ML, Rosen PP. Multinucleated stromal giant cells in mammary fibroepithelial neoplasms. A study of 11 patients. Arch Pathol Lab Med 1994; 118: 912e6. 8 Heneghan HM, Martin ST, Casey M, Tobbia I, Benani F, Barry KM. A diagnostic dilemma in breast pathology e benign fibroadenoma with multinucleated stromal giant cells. Diagn Pathol 2008; 3: 33. 9 Slavin JL, Billson VR, Ostor AG. Nodular breast lesions during pregnancy and lactation. Histopathology 1993 May; 22: 481e5. 10 Ross DS, Giri DD, Akram MM, Catalano JP, Olcese C, Van Zee KJ, Brogi E. Fibroepithelial lesions in the breast of adolescent females: a clinicopathological study of 54 cases. Breast J 2017; 23: 182e92. 11 Tham K-T, Dupont WD, Page DL, Gray GFJ, Rogers LW. Micropapillary hyperplasia with atypical features in female breasts, resembling gnaecomastia. 10th edn. New York: Field and Wood, 1989; 101e9. 12 Mies C, Rosen PP. Juvenile fibroadenoma with atypical epithelial hyperplasia. Am J Surg Pathol 1987; 11: 184e90. 13 Daroca PJ, Reed RJ, Love GL, Kraus SD. Myoid hamartomas of the breast. Hum Pathol 1985; 16: 212e9. 14 Fisher CJ, Hanby AM, Robinson L, Millis RR. Mammary hamartomas e a review of 35 cases. Histopathology 1992; 20: 99e106.
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32 Vera-Sempere F, Garcia-Martinez A. Malignant phyllodes tumor of the breast with predominant chondrosarcomatous differentiation. Pathol Res Pract 2003; 199: 841e5. 33 Lee AH, Hodi Z, Ellis IO, Elston CW. Histological features useful in the distinction of phyllodes tumour and fibroadenoma on needle core biopsy of the breast. Histopathology 2007; 51: 336e44. 34 Yohe S, Yeh IT. ‘‘Missed’’ diagnoses of phyllodes tumor on breast biopsy: pathologic clues to its recognition. Int J Surg Pathol 2008; 16: 137e42. 35 Coyne JD. Periductal stromal hyperplasia. Histopathology 2007; 50: 814e5. 36 Burga AM, Tavassoli FA. Periductal stromal tumor: a rare lesion with low-grade sarcomatous behavior. Am J Surg Pathol 2003; 27: 343e8.
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The biological distinction between fibroadenomas and benign phyllodes tumours is blurred and may represent a biological continuum Features within fibroepithelial lesions that predict recurrences and metastasis are the most important ones to determine Classification of borderline and malignant phyllodes tumours requires judgement based on a number of features, no single features alone Juvenile fibroadenoma may show marked stromal cellularity and mitotic activity but this is matched by that seen in the epithelial compartment of these lesions
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Fibroepithelial neoplasms of the breast
hides the fact that there a number of unclear areas. For some categories these considerations may not be important; for example, whether lactating adenoma is an entity in its own right or a fibroadenoma with superimposed lactational change. For others these considerations are more significant; phyllodes tumours include some lesions that recur and some lesions that are malignant.
Andrew M Hanby Rebecca Millican-Slater Benjamin Dessauvagie
Fibroadenoma e conventional type These are harmless lesions and if tissue diagnosis is made, typically by core biopsy, there is an increasing tendency for them to be left and not excised, although continued growth and/or late presentation may prompt surgery. Fibroadenomas are well-defined lesions which may be multiple in up to 20% of cases. They are clearly delineated from the surrounding breast and, as a consequence, can be quite mobile within the breast, hence the term ‘breast mice’ is sometimes used. There is a great variation in size. Typically they are firm and rubbery, but can be hard on the rare occasion when there is internal calcification. Often they have a bosselated gross appearance and have a white cut surface, with clefting sometimes discernible on macroscopic examination. As indicated above these tumours represent co-proliferations of epithelium and stroma with both elements growing in concert. Traditionally, intracanalicular variants, with the epithelium arranged in clefts, and pericanalicular variants, where the epithelium is arranged in rounded acini-like configurations, are identified, although elements of both can commonly be seen in the same lesion (Figure 1). Stroma is of uniform cellular density which varies from almost acellular in long-standing, hyaline variants, to highly cellular in so e called ‘cellular fibroadenoma’. Neither the intracanalicular nor the pericanalicular pattern has any particular clinical connotation, although since the former is also seen in phyllodes tumours, intracanalicular fibroadenomas are those most likely to cause diagnostic difficulty.
Abstract Fibroepithelial neoplasms include a large number of common lesions encountered in both symptomatic and breast screening practice. Nearly all are fibroadenomas and are harmless, but they can present a range of differing histologies. The area of most concern is the separation of fibroadenomas from phyllodes tumours, arguably an arbitrary exercise at the benign end of the spectrum. What is most important to achieve is the recognition of those lesions in the fibroadenoma-phyllodes spectrum with the potential to do harm, either in the form of recurrence or metastases. These are few in number and the key features to identify, with the rare exception of carcinoma arising in these lesions, are those that signify a progression to stromal autonomy. Such features include stromal overgrowth, stromal invasion, stromal cell atypia and stromal mitotic activity. These need to be analysed together, not in isolation. Necrosis and heterotypic elements in particular are suggestive of frank malignancy.
Keywords fibroadenoma; hamartoma; lactating adenoma; phyllodes tumour; tubular adenoma
Introduction This review is concerned with neoplasms characterized by a coproliferation of epithelium and stroma. Under this heading come a number of benign lesions such as lactating adenoma, tubular adenoma, fibroadenoma and the low grade end of the phyllodes tumour spectrum. At the other end of the spectrum are borderline and malignant phyllodes tumours. For some malignant phyllodes tumours only a sparse residual epithelial component may remain. The classifications of these lesions are morphology based and in many cases the comfort zone provided by pigeonholing entities into specified nomenclature
Fibroadenoma e epithelial proliferations Fibroadenomas may show a number of epithelial phenomena superimposed on their basic architecture; for example, usual ductal hyperplasia, sclerosing adenosis, squamous metaplasia and lactational change. ‘Complex fibroadenoma’ is recognised where there is one or more of the following features: papillary apocrine hyperplasia, cysts over 3 mm in size and epithelial calcifications (Figure 2).1 Up to 16% of fibroadenomas fall into this category.2 Recent large population studies have indicated that the long held belief of a modest increase in malignancy following a diagnosis of complex fibroadenoma,2 is actually due its frequent associated with other, well established risk factors such as proliferative breast disease and not the complex fibroadenoma itself.3 Fibroepithelial neoplasms and particularly phyllodes tumours are more prone to containing coexisting carcinoma, of which in-situ malignancy is most common; in situ ductal and lobular carcinoma have both been described at relatively equal frequency.4 Invasive carcinoma is less common and, where this is detected, it is important to ascertain whether it is wholly confined to the dominant lesion or has extended into it from the rest of the breast.
Andrew M Hanby FRCPath is a Professor of Pathology at the Leeds Institute of Molecular Medicine, and the Yorkshire Cancer Research & Liz Dawn Pathology and Translational Sciences Centre, St James’s University Hospital, Leeds, UK. Conflicting interests: none. Rebecca Millican-Slater FRCPath is a Consultant Pathologist at Leeds Teaching Hospitals NHS Trust, Leeds, UK. Conflicting interests: none. Benjamin Dessauvagie FRCPA is a Consultant Anatomical Pathologist at PathWest Laboratory Medicine, Fiona Stanley Hospital, Western Australia, Australia and an Adjunct Senior Lecturer in the School of Pathology and Laboratory Medicine at the University of Western Australia. Conflicting interests: none.
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PATHOLOGY OF BENIGN BREAST DISEASE
Figure 3 Myxoid fibroadenoma. A fibroepithelial neoplasm with a sharp interface with adjacent fat. The stroma is distinctly loose, mucoid and relatively acellular, and grossly the cut surface of the lesion is glistening with an almost translucent look. Figure 1 Fibroadenoma. Example of a typical, mostly intracanalicular pattern, fibroadenoma in core biopsies. The cores show no fragmentation and are mostly comprised of a co-proliferation of epithelium and stroma, the latter forming a sharp interface with adjacent fat. The stromal cellularity is low and there is no obvious condensation of stromal nuclei.
Figure 4 Pattern of mucoid change sometimes seen in primary pigmented adrenocortical disease (Carney complex). Here scattered mucoid change is seen in the breast, not specifically forming a distinct ‘adenoma’. It is not known if this example was a proven Carney complex case.
myxomas, cutaneous myxomas, spotty pigmentation and endocrine hyperactivity and is associated with abnormalities in the PRKAR1A gene.5 In one case known to the authors, the diagnosis of the breast lesion pre-dated identification of a left atrial myxoma. In lesions associated with this syndrome, the stroma is extremely loose. Indeed, such loose myxoid change can be seen within the breast stroma divorced from any defined lesion with characteristics of a fibroadenoma6 (Figure 4) and this change may be more obvious in the inter- rather than intra-lobular stroma. It should be noted that most myxoid fibroadenomas are not associated with Carney complex and do not have any harmful associated conditions.
Figure 2 Complex fibroadenoma. Core biopsy showing early sclerosing adenosis and apocrine metaplasia with cyst formation and occasional calcifications.
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Fibroadenomas exhibit varied, sometimes worrying appearances, due to diverse benign stromal and epithelial changes Carcinoma may rarely occur in fibroadenomas
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Fibroadenoma e myxoid Some fibroadenomas have a very loose myxoid matrix with a glistening cut surface (Figure 3). Lesions of this type have been associated with the rare Carney complex, which includes cardiac
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Myxoid fibroadenomas may, rarely, be associated with other systemic abnormalities as part of Carney complex
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PATHOLOGY OF BENIGN BREAST DISEASE
may show infarction and this can be extensive (Figure 6). Whilst in some lesions the vestige of a fibroadenoma or tubular adenoma can suggest a derivation from it, in other cases it is less clear that this lesion is a tumour and instead represents merely a dominant lactating lobe.9 These lesions are important in so much as they may present as a hard mass during pregnancy and therefore raise concern. Their diagnosis is usually straightforward and, of themselves, have no serious clinical implications.
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Figure 5 Stromal giant cells. Such cells may be seen in a variety of fibroepithelial neoplasm and are sometimes numerous. This example is within a borderline phyllodes tumour. Such cells do not carry any specific behavioural connotations.
Tubular adenoma As originally described, these tumours comprise closely packed tubules with little intervening stroma and, in some examples, prominent lymphocytes. Observation of the practice of fellow pathologists suggests that there is diagnostic terminological drift to include lesions where the glands may not be so well packed and stroma more evident (Figure 7). Additionally, lesions with hybrid fibroadenoma features are also seen.9 In any event, these lesions have no harmful implications.
Fibroadenomas with multinucleated stromal giant cells On occasion an otherwise typical fibroadenoma may contain bizarre, pleomorphic and/or hyperchromatic fibroblasts7,8 (Figure 5). These may be plentiful and unnerving to the unwary. Crucially these rarely have associated stromal mitoses. They may also be seen in phyllodes tumours.7 Such fibroblasts are not associated with any behavioural significance in either fibroadenomas or phyllodes tumours.
Juvenile fibroadenoma The presentation of these lesions may be alarming with rapid growth and distortion of the breast sometimes seen.10 Such a presentation combined with what can be a very striking histological picture may suggest a phyllodes tumour (see below) to the unwary. Grossly juvenile fibroadenomas are well-defined and encapsulated masses. Microscopically, mitotic activity and stromal cellularity may be very marked. Unlike phyllodes tumour,
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‘Lactating’ adenomas may infarct
Giant cells in fibroepithelial neoplasms are generally of no significance
Lactational/lactating adenoma As might be expected, these lesions occur during pregnancy and during lactation. They may be quite large and biopsies reveal a mass of closely packed lactating acini/glands On occasion these
Figure 7 ‘Tubular adenoma’. A lesion which many pathologists would now call a tubular adenoma being comprised largely of tubular components. An excess of lymphocytes is seen and is a common accompaniment of these lesions. It is important to note that lesions like the one illustrated here do not fulfil the criteria for tubular adenoma as originally described, since classic examples should show little or no surrounding fibrous stroma and often have very inconspicuous myoepithelium. Perfect examples are, in this author’s experience, very rare.
Figure 6 Lactating adenoma. Core biopsy showing infarction with a peripheral subcapsular rim of viable adenomatous tissue.
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PATHOLOGY OF BENIGN BREAST DISEASE
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Figure 9 Myoid differentiation in a fibroadenoma. This fibroadenoma shows both sclerosing adenosis towards the top and clear myoid differentiation (towards the middle and bottom of the core). If there is any doubt the lesion can be stained for markers to desmin which will illuminate the slips of smooth muscle. Such a change may be focal or extensive throughout the lesion, in which case the label myoid hamartoma can be used, although this does not carry with it any specific behavioural associations.
Myoid hamartomas/fibroadenomas with myoid differentiation Some benign fibroepithelial neoplasms show smooth muscle differentiation within the stroma, which may on occasion be striking but more often can be seen as a localized change. The smooth muscle cells will, as elsewhere, label with both smooth muscle actin and myosin. Such differentiation is not, of itself, associated with any particular biology, but where prominent may produce an unexpected appearance. Whilst some have related these lesions to mammary hamartomas (see below),13 in the authors’ experience others look more like fibroadenomas with extensive myoid differentiation (Figure 9).
b Juvenile fibroadenoma.a Stromal expansion and hypercellularity. b Detail of this illustrating gynaecomastoid epithelial hyperplasia in addition to stromal (A) and epithelial (B) mitoses (also insets). Figure 8 Juvenile fibroadenoma. (a) Stromal expansion and hypercellularity. (b) Detail of this illustrating gynaecomastoid epithelial hyperplasia in addition to stromal (A) and epithelial (B) mitoses (also insets).
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however, in juvenile fibroadenoma diffuse stromal cell atypia is absent, there is no relative stromal overgrowth, a pericanalicular architecture is seen and increased mitotic activity in the stroma (which can number up to seven per 10 high power fields (10 HPFs)) is matched by that seen in the epithelium (Figure 8). Often the epithelium may show a distinct pattern of epithelial proliferation whereby the hyperplasia resembles that seen in gynaecomastia.11 This ‘gynaecomastoid hyperplasia’ is distinctive of these lesions. In some rare cases atypical epithelial proliferations are seen.12 The clinical outcome of juvenile fibroadenoma is no different to conventional fibroadenoma.10
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Mammary hamartoma and pseudoangiomatous stromal hyperplasia Whether mammary hamartoma qualifies as a fibroepithelial neoplasm is debatable. Certainly these enigmatic lesions do not fit the dictionary description of a ‘hamartoma’. They warrant a place in this review as they are lesions that manifest as welldefined breast masses which clinically and radiologically can resemble fibroadenomas. On excision they are also well defined, typically with a white cut surface. In the authors’ experience they are more rubbery and softer than classic fibroepithelial lesions and are more compressible. These lesions typically contain the constituents of normal/benign breast tissue and a core biopsy may not present a distinctive picture from the rest of the breast.
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Juvenile fibroadenomas show both stromal and epithelial hyperplasia The hyperplasia is typically florid and resembles that seen in gynaecomastia e hence the term gynaecomastoid
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these examples often fall easily into one category or another, and are not the ‘grey’ examples seen in working practice with overlapping features that are open to subjective analysis. Perusal of the large amount of literature on phyllodes tumours and fibroadenomas reveals a range of appearances and biological features. This is matched by diversity in the number of different cut-offs devised by different groups and purporting to distinguish between the different categories. Some understanding of the known molecular, cytogenetic and cell biological features underlying these lesions can help to make some sense of what is going on and to make a judgement of the likely behaviour of such lesions. Benign fibroepithelial lesions represent a good illustration of the phenomenon of epithelial-stromal cross-talk. In benign lesions the stromal and epithelial elements grow in concert because they influence each other either through direct cell contact or secreted products, and most likely both. We know very little if anything about what initiates these lesions. In some examples of phyllodes tumours, loss of heterozygosity (LOH) studies show that abnormalities can exist in either the stroma or the epithelium,15 but this does not per se imply that they are causative. In both fibroadenomas and most phyllodes tumours, mRNA for the wnt molecules, 5a and two, can be detected; 5a in the epithelium and two in both the epithelium and stroma. The changes are more pronounced in the group classified as phyllodes than those classified as fibroadenoma using traditional criteria, but do not permit clear cut-offs between these groups. The wnts are able to influence a number of signalling pathways; for example, wnt2 can lead to upregulation of transcriptionally active b-catenin, which in turn is able to effect proliferation via upregulation of a variety of effectors of which cyclin D1 and cmyc are examples.16 This is what is seen in fibroadenomas and most phyllodes tumours, with b-catenin demonstrable in the stromal nuclei and also, most markedly in the phyllodes group, an increase in c-myc and cyclin D1. Furthermore, upregulation of insulin-like growth factor 1(IGF1) mRNA can be shown in the stromal components of these tumours, whilst one of its receptors, IGFR1, is expressed on the epithelial cells. This interaction could represent an alternate mechanism of nuclear b-catenin accumulation in some fibroepithelial neoplasms.17 These observations together show how each component in these lesions can sustain the other and that the molecular observations between most lesions we call phyllodes and those we call fibroadenomas are shared. The situation changes dramatically at the malignant phyllodes end of the spectrum. In these tumours the stromal element shows no nuclear b-catenin, the wnts are not upregulated and new abnormalities such as c-kit, PAX3, SIX1, HMGA2 and TGFB1 upregulation, c-myc and EGFR1 amplification, and p16INK4a inactivation can be demonstrated.18e20 Furthermore, there is more frequent LOH and increasing complex karyotypic changes.20,21 Such abnormalities reflect a stromal population no longer dependent on the epithelial crosstalk and now autonomous. In summary, when making individual decisions to fit a lesion into the conventional categories, it is important to realize that these categories are not set in stone, that their borders are blurred and that fibroadenomas and phyllodes tumours may form part of one spectrum, a difficulty reflected in other
Figure 10 Mammary hamartoma. Photomicrograph of a portion of a sample from a radiologically and clinically well-defined lesion. It shows very marked pseudoangiomatous hyperplasia (PASH), a phenomenon characterized by a collagenous stroma exhibiting marked clefting resembling the slit-like spaces seen in some vascular neoplasms. The histology of hamartomas is very variable and samples from lesions show a histology inseparable from normal breast tissue.
Only radiological proof of origin of the examined tissue from a well-defined mass permits diagnosis. However, the stroma is often distinctive and shows pseudoangiomatous stroma hyperplasia (PASH) (Figure 10). This is characterized by a rather sclerotic matrix containing slit-like spaces arranged in a manner resembling angiomatous blood vessels. Associated stromal cells are CD34 positive but do not mark with specific markers of vasculature and probably represent myofibroblasts.14 This change is sometimes seen as a localized isolated phenomenon. Some authorities regard PASH as a lesion in its own right and indeed many regard mammary hamartomas as PASH.
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Hamartomas are well-defined lesions without the typical architecture of fibroadenomas PASH is commonly seen in hamartomas PASH may be seen in isolation
Phyllodes tumours and the fibroadenoma e phyllodes tumour spectrum At the heart of most concerns about fibroepithelial lesions is their distinction from phyllodes tumours. Phyllodes tumours form a spectrum from benign, through borderline, to malignant. There is a greater propensity to recur and, less commonly, to metastasize away from the benign ‘end’ of this spectrum. These behavioural traits distinguish these lesions, in the main, from fibroadenomas and for this practical reason many standard texts separate fibroadenomas from phyllodes tumours as clearly defined entities. In reality most tumours defined as phyllodes tumour do not recur. Furthermore, while many texts give illustrative examples of these classic lesions and compare them to fibroadenomas,
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PATHOLOGY OF BENIGN BREAST DISEASE
publications.22,23 Understanding the biology will help in making realistic judgements based on morphology. What follows is a reiteration of standard convention governing these lesions.
frank pleomorphism (Figure 11) being more typical of malignant phyllodes tumours and affecting more of the neoplastic stromal cells. As noted above, bizarre giant cells may not per se be indicative of malignancy.7 Stromal mitoses Fibroadenoma versus benign phyllodes tumours: in general, mitoses are very rare in fibroadenomas and few in number in benign phyllodes tumour, and are not the most useful distinguishing feature. However, it should be remembered that mitotic activity within juvenile fibroadenomas may be very high, but is matched by epithelial mitotic activity which is equivalently high within the context of that lesion (see above).
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Morphological and molecular evidence does not indicate such clear differences between some fibroadenomas and phyllodes tumours as some texts imply In benign fibroepithelial neoplasms the stroma and epithelium show evidence of ‘cross-talk’ and co-proliferation Malignant phyllodes tumours develop stromal autonomy
Benign versus borderline versus malignant phyllodes Tumours: in this spectrum the number of mitoses increases from benign through to malignant phyllodes tumours. There is variety in the cut off point suggested between different groups and whilst many regard this as one of the most important features in the differentiation of these groups, it is difficult to define a clear consensus, not least because many of the papers do not, for example, take into account field size in the mitotic counting.28 In the most recent WHO guidelines mitotic activity is described as ‘usually few’ with a cut-off of <5 per 10 HPFs for benign, ‘usually frequent’ (5e9 per 10 HPFs) for borderline and ‘usually abundant’ (10 per 10 HPFs) for malignant tumours.25 It is worth noting that the mitotic activity and cellularity often go hand in hand and there may be regional variation, and thus careful examination of the whole lesion and adequate sampling should be factored into the analytical process.
General clinicopathological features of phyllodes tumours These lesions occur most commonly in the 40e50-year age group.24,25 Although some have noted a lower age incidence in Asian populations, for example 25e30 years in a study by Chua et al.,22 in a series of 453 cases from Singapore the mean age was 42 years,19 similar to ‘Western’ populations. Gross As expected, lesions at the benign end of the spectrum, where they merge with fibroadenomas, do not differ from fibroadenomas in appearance. With borderline and malignant lesions the boundaries with surrounding tissue are less clearly defined, correlating with the increasing propensity to an infiltrative growth pattern. Additionally, in frankly malignant lesions, more fleshy large tumours with softening and cavitation associated with necrosis are seen.
Stromal cellularity Fibroadenoma versus benign phyllodes tumours: in general, phyllodes tumours are more cellular than fibroadenomas. However, this analysis is subjective23 and some lesions that are fibroadenomas in every other way may have a cellular stroma (cellular fibroadenoma, see above). More important is the
Histology Like fibroadenomas, benign phyllodes tumours represent a coproliferation of stroma and epithelium growing in concert. Progressing along the spectrum through borderline to malignant there is a progression of histological features. These features are stromal-to-epithelial ratio, the interface between the lesion and surrounding breast tissue, stromal cellularity, stromal (and epithelial) mitotic activity, stromal cell atypia and whether there is stromal necrosis. The combinations of these features are many and therefore for individual cases, judgement more than dogma is required. In assessing a fibroepithelial neoplasm in this spectrum, it is important that sampling is thorough as the morphology and indeed the cytogenetic profile may be heterogeneous.26 The proposal that grading is based on the worst area, as long as it is equal to or exceeds 10% of the tumour, is a reasonable strategy.27 The effect of fixation on such features such as mitotic activity should also be considered. Stromal cell atypia Fibroadenoma versus benign phyllodes tumours: in general, the fibroblasts in both these circumstances are relatively bland and nuclear pleomorphism is rarely a criterion used to separate them.
Figure 11 Malignant phyllodes tumour. This sample from a core biopsy displays not only the cellular stromal condensation next to the epithelium seen in many phyllodes tumours, but also the increased stromal cellularity, nuclear hyperchromasia and pleomorphism that may be seen.
Benign versus borderline versus malignant phyllodes Tumours: with progression from benign to malignant there is an increase in nuclear pleomorphism, with hyperchromasia and
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distribution of the cellularity. In typical phyllodes tumours enhanced stromal cellularity is seen immediately beneath the epithelial element (Figure 11) and can appear quite pronounced on low power examination. In some cases, however, the condensation may be more pronounced remote from the epithelium (Figure 12).
Benign versus borderline versus malignant phyllodes Tumours: Lesions along this spectrum show an increasing tendency towards having a blurred/infiltrative interface with adjacent breast tissue, with the stromal element extending out into these tissues (Figure 13). This may be focal and limited in borderline lesions through to overtly and widely invasive in malignant examples. Where there is apparent recurrence after a previous excision, the analysis may be particularly challenging as the fibroblasts associated with the repair changes may resemble neoplastic fibroblasts and confound analysis of excision margins.
Benign versus borderline versus malignant phyllodes Tumours: In general, from benign through to malignant there is an increase in stromal cellularity with malignant lesions often very highly cellular (see Figure 11). Stromal overgrowth Fibroadenoma versus benign phyllodes tumours: Typically, phyllodes tumours have a higher stromal-to-epithelial ratio than fibroadenoma. However, at the benign end of the spectrum this is very subjective, the ratio varies between different fibroadenomas and on this feature alone the entities merge.
Architecture This is partly a manifestation of the effects of the features additionally described in this section. Classic phyllodes tumours have an intracanalicular rather than a pericanalicular growth pattern, with clefting being a typical feature. This of itself does not make the diagnosis, but the scale of the clefting is larger and the clefts are often wider and occasionally cystic. This partly accounts for one of the archetypal features of these lesions: the leaf-like configurations of bulging stroma overlain by epithelium (Figure 14). Analysis of even this feature is subjective and the other attributes must be taken into account.
Benign versus borderline versus malignant phyllodes Tumours: As indicated above, in both fibroadenomas and phyllodes tumours there is cross-talk between the epithelium and stroma with growth of one affecting the other. As autonomy of the stromal element develops, this is lost. This is reflected in the histology with increasing stroma relative to epithelium evident in the progression from benign, through borderline to malignant. In the latter, extreme parts of the lesion may be purely stroma, referred to as stromal overgrowth and arbitrarily defined as the presence of epithelium-free microscopic fields, and/or take on the appearances of a malignant spindle cell neoplasm.
Frank malignancy and heterologous elements Despite the criteria discussed above, correlation with behaviour is not perfect, and while most patients will not experience problems, occasionally apparent low-grade tumours will recur.29 At the malignant end, as indicated above, phyllodes tumours can show a frankly sarcomatous pattern characterized by a mitotically active, pleomorphic, cellular and invasive growth of neoplastic stromal cells and areas of tumour-cell necrosis. Faced with a sarcomatous lesion from the breast, a diligent search for remnant phyllodes architecture is essential to differentiate a pure stromal tumour/sarcoma from a malignant phyllodes tumour.
Interface between the lesion and the normal breast tissue Fibroadenoma versus benign phyllodes tumours: Both these lesions nearly always show a sharp interface with clear definition from adjacent breast tissue, and this feature does not serve to distinguish them.
Figure 12 Borderline phyllodes tumour. This illustrates a phyllodes tumour in which cellular stromal condensation is seen remote from the epithelium with a more subtle increase in cellularity next to the epithelium. It is important to note that for lesions such as this, all factors need to be taken into account in the assignment to a category. The prominent epithelium is in this regard a reassuring feature.
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Figure 13 Malignant phyllodes tumour. This demonstrates an extensively invasive tumour. The likelihood is that the epithelium seen here represents adjacent breast epithelium rather than the original lesional epithelium. Note the propensity for the stroma to condense around the epithelium and a field such as this resembles the appearances of periductal stroma tumour.
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PATHOLOGY OF BENIGN BREAST DISEASE
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Core biopsy of fibroepithelial lesions The interpretation of a core biopsy containing a fibroepithelial neoplasm has important management consequences. Generally, where a lesion is considered to be a fibroadenoma, no further action is taken. However, for a lesion interpreted as a phyllodes tumour or suspicious for a phyllodes tumour, excision of the lesion with a surrounding margin of benign tissue is recommended practice; ‘shelling out’ of the lesion is inappropriate and more likely to lead to recurrence in phyllodes tumours. Because of sample size and the reduced ability to see the overall tumour architecture, the differential diagnosis between fibroadenoma and phyllodes tumour is more of a challenge on needle core biopsies. Additionally, the sample may not even be from the most diagnostic area, so a core from a large lesion may not be representative. Of potential use diagnostically, in addition to the traditional features described above such as stromal cellularity and mitoses, the phenomenon of biopsy fragmentation occurs more commonly in phyllodes tumours than in fibroadenomas.33,34
Figure 14 Benign phyllodes tumour. This illustrates the classic architecture of phyllodes tumours with an exaggerated intracanilicular growth pattern with bulging stroma pushing into the epithelial-lined slits creating the so-called leaf-like pattern. Some of these spaces may become cystic.
Immunohistochemistry of fibroepithelial lesions A great number of molecular markers have been proposed to assist in this distinction. The basic science behind the biology of phyllodes tumours, as detailed above, gives some clue as to markers that could be of use; for example, the observation that there is downregulation of nuclear b-catenin in malignant phyllodes tumours could be of practical benefit. However, loss of a marker is never as attractive as acquisition, as when faced with a negative result there is always doubt regarding whether a test has worked. Some advocate strongly the value of CD34 as a positive marker in phyllodes tumours but not in fibromatoses or spindle cell carcinomas, from which distinction sometimes has to be made.23 Broadly speaking, however, morphology remains the mainstay in assigning a tumour to its position in the fibroadenoma-phyllodes spectrum.
Figure 15 Malignant phyllodes tumour. Heterologous osseous focus. Elsewhere in this lesion chondrosarcomatous elements were also found.
Phyllodes tumours can show diverse and often extensive heterologous malignant elements, including osteo-, chondro- and liposarcomatous differentiation (Figure 15).30,31,32 Indeed, such heterologous elements and necrosis were the only features shown to be significant in predicting metastasis-free and overall survival in a series of 77 phyllodes tumours in a multivariate analysis.24 Metaplastic carcinoma is outside the scope of this chapter, except to say that in some examples the combination of malignant spindle cells and more obvious glandular elements may suggest a fibroepithelial neoplasm and heterologous elements may be present. One of the key clues is the co-existence of both malignant glandular and stroma elements and the immunohistochemical detection of epithelial differentiation. Useful markers that may be positive in this regard include CAM5.2, CK5, CK14 and p63.
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Classifying fibroepithelial lesions along the fibroadenomaphyllodes spectrum requires assessment of a number of features and often a judgement call Necrosis and heterologous elements are highly indicative of a malignant lesion Heterologous elements may be seen in some metaplastic carcinomas
Periductal stromal tumour Periductal stromal tumour is a rare condition probably related to phyllodes tumours. Grossly they may appear multinodular. Microscopically neoplastic stromal cells, similar in cytological characteristics to conventional phyllodes tumours, insinuate diffusely around and spread along open mammary ducts, forming variably cellular cuffs. There is absence of the typical phyllodes ‘leaf-like’ architecture. Stromal cell CD34 positivity is noted.23 Some variation in nomenclature has occurred in the literature; periductal stromal sarcoma has been used to denote a
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PATHOLOGY OF BENIGN BREAST DISEASE
locally aggressive lesion with three or more mitoses per HPF and stromal nuclear atypia while periductal stromal hyperplasia has been used to described a benign lesion with bland stroma and rare mitoses.35,36 A
15 Sawyer EJ, Hanby AM, Ellis P, et al. Molecular analysis of phyllodes tumors reveals distinct changes in the epithelial and stromal components. Am J Pathol 2000; 156: 1093e8. 16 Sawyer EJ, Hanby AM, Rowan A, et al. The Wnt pathway, epithelialstromal interactions, and malignant progression in phyllodes tumours. J Pathol 2002; 196: 437e44. 17 Sawyer EJ, Hanby AM, Poulsom R, et al. Beta-catenin abnormalities and associated insulin-like growth factor overexpression are important in phyllodes tumours and fibroadenomas of the breast. J Pathol 2003; 200: 627e32. 18 Sawyer EJ, Poulsom R, Hunt FT, et al. Malignant phyllodes tumours show stromal overexpression of c-myc and c-kit. J Pathol 2003; 200: 59e64. 19 Tse GM, Lui PC, Vong JS, et al. Increased epidermal growth factor receptor (EGFR) expression in malignant mammary phyllodes tumors. Breast Cancer Res Treat 2009; 114: 441e8. 20 Karim RZ, O’Toole SA, Scolyer RA, et al. Recent insights into the molecular pathogenesis of mammary phyllodes tumours. J Clin Pathol 2013 Jun; 66: 496e505. http://dx.doi.org/10.1136/jclinpath-2012-201082. Epub 2013 Feb 12. 21 Lv S, Niu Y, Wei L, Liu Q, Wang X, Chen Y. Chromosomal aberrations and genetic relations in benign, borderline and malignant phyllodes tumors of the breast: a comparative genomic hybridization study. Breast Cancer Res Treat 2008; 112: 411e8. 22 Chua CL, Thomas A, Ng BK. Cystosarcoma phyllodes e Asian variations. Aust N Z J Surg 1988; 58: 301e5. 23 Lee AH. Recent developments in the histological diagnosis of spindle cell carcinoma, fibromatosis and phyllodes tumour of the breast. Histopathology 2008; 52: 45e57. 24 Cohn-Cedermark G, Rutqvist LE, Rosendahl I, Silfversward C. Prognostic factors in cystosarcoma phyllodes. A clinicopathologic study of 77 patients. Cancer 1991; 68: 2017e22. 25 Lakhani SR, Ellis IO, Schnitt SJ, eds. Pathology and genetics of tumours of the breast. Lyon: IARC Press, 2012. 26 Jones A, Mitter R, Springall R, et al. A comprehensive genetic profile of phyllodes tumours of the breast detects important mutations, intra-tumoral genetic heterogeneity and new genetic changes on recurrence. J Pathol 2008; 214: 533e44. 27 Moffat CJ, Pinder SE, Dixon AR, Elston CW, Blamey RW, Ellis IO. Phyllodes tumours of the breast: a clinicopathological review of thirty-two cases. Histopathology 1995; 27: 205e18. 28 Millis RR, Hanby AM, Oberman HA. The breast. In: Sternberg SS, ed. Diagnostic surgical pathology, vol. 1. New York: Raven Press, 1999; 319e85. 29 Rowell MD, Perry RR, Hsiu JG, Barranco SC. Phyllodes tumors. Am J Surg 1993; 165: 376e9. 30 Kefeli M, Yildiz L, Akpolat I, Balci P, Ozen N. The coexistence of invasive ductal carcinoma and malignant phyllodes tumor with liposarcomatous and chondrosarcomatous differentiation in the same breast in a post-osteosarcoma case. Pathol Res Pract 2008; 204: 919e23. 31 Norris HJ, Taylor HB. Relationship of histologic features to behavior of cystosarcoma phyllodes. Analysis of ninety-four cases. Cancer 1967; 20: 2090e9.
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32 Vera-Sempere F, Garcia-Martinez A. Malignant phyllodes tumor of the breast with predominant chondrosarcomatous differentiation. Pathol Res Pract 2003; 199: 841e5. 33 Lee AH, Hodi Z, Ellis IO, Elston CW. Histological features useful in the distinction of phyllodes tumour and fibroadenoma on needle core biopsy of the breast. Histopathology 2007; 51: 336e44. 34 Yohe S, Yeh IT. ‘‘Missed’’ diagnoses of phyllodes tumor on breast biopsy: pathologic clues to its recognition. Int J Surg Pathol 2008; 16: 137e42. 35 Coyne JD. Periductal stromal hyperplasia. Histopathology 2007; 50: 814e5. 36 Burga AM, Tavassoli FA. Periductal stromal tumor: a rare lesion with low-grade sarcomatous behavior. Am J Surg Pathol 2003; 27: 343e8.
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The biological distinction between fibroadenomas and benign phyllodes tumours is blurred and may represent a biological continuum Features within fibroepithelial lesions that predict recurrences and metastasis are the most important ones to determine Classification of borderline and malignant phyllodes tumours requires judgement based on a number of features, no single features alone Juvenile fibroadenoma may show marked stromal cellularity and mitotic activity but this is matched by that seen in the epithelial compartment of these lesions
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Please cite this article in press as: Hanby AM, et al., Fibroepithelial neoplasms of the breast, Diagnostic Histopathology (2017), http://dx.doi.org/ 10.1016/j.mpdhp.2017.03.012