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Fibroepithelial neoplasms of the breast
SYMPOSIUM: PATHOLOGY OF BENIGN BREAST DISEASE
Fibroepithelial neoplasms of the breast
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, or even 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 pericanilicular 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). Neither pattern has any particular clinical connotation, although since the intracanilicular pattern is also seen in phyllodes tumours, fibroadenomas with this pattern are those most likely to cause diagnostic difficulty.
Andrew M Hanby
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. What is most important to achieve is the recognition of those lesions in the fibroadenomaephyllodes 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 outgrowth, stromal invasion and both stromal atypia and pleomorphism. These need to be analysed together, not in isolation. Necrosis and heterotypic elements in particular are suggestive of frank malignancy.
Fibroadenoma e epithelial proliferations Fibroadenomas may show a number of epithelial phenomena imposed upon their basic architecture; for example, usual type ductal hyperplasia, sclerosing adenosis, squamous metaplasia and around pregnancy and after lactational change. Additionally there is the ‘complex fibroadenoma’ in which 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 Although some population studies have indicated that there is a modest increase in malignancy following a diagnosis of complex fibroadenoma (3.1 general population) versus a diagnosis of fibroadenoma (1.89 general population),1 the magnitude is
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 phyllodes tumour spectrum. For some malignant phyllodes tumours only a sparse residual epithelial component may remain. The classifications of many of these lesions are morphology based and in many cases the comfort zone provided by pigeonholing entities into specified nomenclature 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 important; phyllodes tumours include some lesions that recur and some lesions that are malignant.
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.
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.
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.
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Figure 2 Complex fibroadenoma. Core biopsy showing early sclerosing adenosis and apocrine metaplasia with cyst formation and occasional calcifications.
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.
such as to have no clinical implications for the individual case and treatment should be as for straightforward fibroadenomas.2 Fibroepithelial neoplasms and particularly phyllodes tumours are more prone to containing co-existing carcinoma, of which in-situ malignancy is most common; both ductal and lobular have been described although lobular carcinoma in situ (LCIS) is most common. 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.
myxoid fibroadenomas are not associated with PPNAD and do not have any harmful associated conditions.
Practice point C
Mxyoid fibroadenomas may, rarely, be associated with other systemic abnormalities as part of PPNAD.
Practice points Fibroadenomas with multinucleated stromal giant cells C C
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Fibroadenomas may show diverse benign epithelial changes. Complex fibroadenomas are associated with in breast cancer risk in large populations but is not enough to have implications for the individual patient. Carcinoma may rarely occur in fibroadenomas
On occasion an otherwise typical fibroadenoma may contain bizarre fibroblasts5,6 (Figure 5). These may be plentiful and unnerving to the unwary. Crucially these rarely have associated stomal mitoses and may also be seen in phyllodes tumours5; such fibroblasts are not associated with any behavioural significance in either fibroadenomas or phyllodes tumours.
Practice point Fibroadenoma e myxoid C
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, more recently encompassed under the title primary pigmented adreonocortical disease (PPNAD) and associated with abnormalities in the PRKAR1A gene.3 This complex also can include cardiac myxomas, cutaneous myxomas and spotty pigmentation,4 as well as other soft tissue tumours and endocrine hyperactivity. In one case known to this author, 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 myxyoid change can be seen within the breast stroma divorced from any defined lesion with characteristics of a fibroadenoma4 (Figure 4) and this change may be more obvious in the interrather than intra-lobular stroma. It should be noted that most
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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 (Figure 6). On occasion these may show infarction and this can be extensive. Whilst in some lesions the vestige of a fibroadenoma of conventional type can suggest a derivation from it, in other cases it is less clear that this lesion is a tumour or merely a dominant lactating lobe.7 These lesions are important in so much as they
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Figure 6 Lactating adenoma. Core biopsy showing infarction with a peripheral subcapsular rim of viable adenomatous tissue. Figure 4 Pattern of mucoid change sometimes seen in primary pigmented adrenocortical disease (PPNAD). 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 PPNAD case.
to include lesions where the glands may not be so well packed and stroma more evident (Figure 7). In any event, these lesions have no harmful implications. Additionally, lesions with hybrid fibroadenoma features are also seen.7
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.
Juvenile fibroadenoma The presentation of these lesions may be alarming with rapid growth and distortion of the breast sometimes seen.8 Such a presentation combined with what can be a very striking histological picture (see below) may suggest a phyllodes tumour 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, however, in juvenile fibroadenoma there is no relative stromal overgrowth, a pericanalicular architecture is seen and increased mitotic activity in the stroma is matched by that seen in the epithelium (Figure 8). Often the epithelium may show a distinct pattern of epithelial proliferation whereby the
Practice point C
‘Lactating’ adenomas may infarct.
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
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 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.
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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.
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),11 in this author’s experience others look more like fibroadenomas with extensive myoid differentiation (Figure 9).
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).
Practice point C
Figure 8
Smooth muscle differentiation may be seen in fibroepithelial neoplasm, some resemble fibroadenomas, others hamartomas
hyperplasia resembles that seen in gynaecomastia.9 This ‘gynaecomastoid hyperplasia’ is distinctive of these lesions. In some rare cases atypical epithelial proliferations are seen.10
Mammary hamartoma and pseudoangiomatous stromal hyperplasia
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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 this author’s 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. 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
Juvenile fibroadenomas show both stromal and epithelial hyperplasia The hyperplasia is typically florid and resembles that seen in gynaecomastia e hence the term gynaecomastoid.
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
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are not the ‘grey’ examples not uncommonly seen in working practice where overlapping features that are open to subjective analysis are seen. 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 epithelialestromal 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,13 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 2, can be detected; 5a in the epithelium and 2 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 c-myc are examples.14 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 can be seen. Thus, the epithelium can influence the stromal growth in this manner. Furthermore, upregulation of insulin-like growth factor 1(IGF1) mRNA can be shown in the stromal components of these, whilst one of its receptors, IGFR1, is expressed on the epithelial cells.15 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 differ in matter of degree without any obvious clear cut-off point. 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 upregulation, and c-myc and EGFR1 amplification16,17 can be demonstrated. Furthermore, there are increasing karyotypic changes.18 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 publications.19,20 Understanding the biology will help in making realistic judgements based on morphology. What follows is a reiteration of standard convention governing these lesions.
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 slitelike 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.
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.12 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.
Practice points C
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Hamartomas are well-defined lesions without the typical architecture of fibroadenomas. PASH is commonly seen in fibroadenomas PASH may be seen in isolation
Phyllodes tumours and the fibroadenomaephyllodes tumour spectrum At the heart of most concerns about fibroepithelial lesions is their distinction from phyllodes tumours. Phyllodes tumours encompass a range of pathologies which can 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, these examples often fall easily into one category or another, and
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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
General clinicopathological features of phyllodes tumours These lesions occur most commonly in the 40e50-year age group.21,22 Although some have noted a lower age incidence in Asian populations, for example 25e30 years in a study by Chua et al,19 in a series of 453 cases from Singapore the mean age was 42 years,17 similar to ‘Western’ populations.
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.
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 mitoses: Fibroadenoma versus benign phyllodes tumours e in general, mitoses are very rare in fibroadenomas and few in number in benign phyllodes tumour, and generally are not the most useful distinguishing feature. However, it should be remembered that mitotic activity within juvenile fibroadenomas may be very high, but this is matched by epithelial mitotic activity which is equivalently high within the context of that lesion (see above).
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 stromalto-epithelial ratio, the interface between the lesion and the normal breast tissue, stromal cellularity, stromal (and epithelial) mitotic activity, stroma 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.23 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.24 The effect of fixation on such features such as mitotic activity should also be considered.
Benign versus borderline versus malignant phyllodes tumours e in this spectrum the number of mitoses increases in the range from benign through to malignant phyllodes tumours. There is variety in the cut 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.25 In the WHO guidelines this is given as ‘few if any’, ‘intermediate’ and ‘numerous (>10 per 10 high-power fields (HPF)).22 This assessment is however context dependent and the view that ‘in the absence of any other worrying features, a mitotic rate of 10 per average (0.44 mm diameter field) 10 HPF’25 is arguably more informative as indicative of malignancy. 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.
Stromal cytology and atypia: Fibroadenoma versus benign phyllodes tumours e in general, the fibroblasts in both these circumstances are relatively bland and nuclear pleomorphism is rarely a criterion used to separate them.
Stromal cellularity: Fibroadenoma versus benign phyllodes tumours e in general, phyllodes tumours are more cellular than fibroadenomas. However, this analysis is subjective20 and some lesions that are fibroadenomas in every other way may have a cellular stroma. More important is the distribution of the cellularity. In typical phyllodes tumours enhanced stromal cellularity is seen immediately beneath the epithelial element (see 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 e with the progression from benign to malignant there is an increase in nuclear pleomorphism, with at the malignant end hyperchromasia and pleomorphism (Figure 11) being more typical of frankly 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.5
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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.
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.
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 e in general, from benign through to malignant there is an increase in stromal cellularity with malignant lesions often very highly cellular (see Figure 11).
Architecture: this is partly a manifestation of the effects of the features additionally described in this section. Classic phyllodes tumours have an intra- rather than a peri-canalicular 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.
Stromal overgrowth: Fibroadenoma versus benign phyllodes tumours e in general, phyllodes tumours have a higher stromal-to-epithelial ratio than fibroadenoma. However, at this end of the spectrum this is very subjective, the ratio varies between different fibroadenomas and on this feature alone the entities merge. Benign versus borderline versus malignant phyllodes tumours e as indicated in the biological overview above, in both fibroadenomas and phyllodes tumours there is a 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 and take on the appearances of a malignant spindle cell neoplasm.
Frank malignancy and heterologous elements in phyllodes tumours Despite the criteria discussed above, the correlation with behaviour is not always good, and most patients will not
Interface between the lesion and the normal breast tissue: Fibroadenoma versus benign phyllodes tumours e 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. Benign versus borderline versus malignant phyllodes tumours e 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
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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.
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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. 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.30,31 Fibroadenoma versus benign phyllodes tumour versus borderline and malignant phyllodes tumour 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.20 Broadly speaking, however, morphology remains the mainstay in assigning a tumour to its position in the fibroadenomaephyllodes spectrum.
Figure 15 Malignant phyllodes tumour. Heterologous osseous focus. Elsewhere in this lesion chondrosarcomatous elements were also found.
experience problems but occasionally apparent low-grade tumours will recur.26 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. 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. Phyllodes tumours can show diverse and often extensive heterologous malignant elements, including osteo-, chondro- and lipo-sarcomatous differentiation (Figure 15).27e29 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.21 Metaplastic carcinoma is outwith 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. Useful markers that will be positive in this regard include CAM5.2, CK5 and CK14.
Periductal stromal tumour This is a rare condition probably related to phyllodes tumours whereby a neoplastic population of stromal cells, similar in cytological characteristics to conventional phyllodes tumours, insinuates itself diffusely around and spreads along mammary ducts, forming a variably cellular cuff. Some variation in nomenclature has occurred in the literature, with the term periductal stromal hyperplasia used in one publication.32 Grossly they may appear multinodular. Burga and Tavassoli encompassed both periductal stromal hyperplasia and sarcoma under the same heading of ‘tumour’ with, at the sarcoma end, three or more mitoses per HPF and stromal nuclear atypia, whilst in the hyperplasias the stroma was bland with only rare mitoses.33 A
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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
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Core biopsy and immunohistochemistry 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
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26 Rowell MD, Perry RR, Hsiu JG, Barranco SC. Phyllodes tumors. Am J Surg 1993; 165: 376e9. 27 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. 28 Norris HJ, Taylor HB. Relationship of histologic features to behavior of cystosarcoma phyllodes. Analysis of ninety-four cases. Cancer 1967; 20: 2090e9. 29 Vera-Sempere F, Garcia-Martinez A. Malignant phyllodes tumor of the breast with predominant chondrosarcomatous differentiation. Pathol Res Pract 2003; 199: 841e5. 30 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. 31 Yohe S, Yeh IT. ‘‘Missed’’ diagnoses of phyllodes tumor on breast biopsy: pathologic clues to its recognition. Int J Surg Pathol 2008; 16: 137e42. 32 Coyne JD. Periductal stromal hyperplasia. Histopathology 2007; 50: 814e5. 33 Burga AM, Tavassoli FA. Periductal stromal tumor: a rare lesion with low-grade sarcomatous behavior. Am J Surg Pathol 2003; 27: 343e8.
associations including cardiac and cutaneous myxomas. Am J Surg Pathol 1991; 15: 713e21. 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. Berean K, Tron VA, Churg A, Clement PB. Mammary fibroadenoma with multinucleated stromal giant cells. Am J Surg Pathol 1986; 10: 823e7. Hertel BF, Zaloudek C, Kempson RL. Breast adenomas. Cancer 1976; 37: 2891e905. Pike AM, Oberman HA. Juvenile (cellular) adenofibromas. A clinicopathologic study. Am J Surg Pathol 1985; 9: 730e6. 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; p. 101e9. Mies C, Rosen PP. Juvenile fibroadenoma with atypical epithelial hyperplasia. Am J Surg Pathol 1987; 11: 184e90. Daroca PJ, Reed RJ, Love GL, Kraus SD. Myoid hamartomas of the breast. Hum Pathol 1985; 16: 212e9. Fisher CJ, Hanby AM, Robinson L, Millis RR. Mammary hamartomas e a review of 35 cases. Histopathology 1992; 20: 99e106. 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. Sawyer EJ, Hanby AM, Rowan A, et al. The Wnt pathway, epithelialstromal interactions, and malignant progression in phyllodes tumours. J Pathol 2002; 196: 437e44. 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. 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. 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. 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. Chua CL, Thomas A, Ng BK. Cystosarcoma phyllodes e Asian variations. Aust N Z J Surg 1988; 58: 301e5. Lee AH. Recent developments in the histological diagnosis of spindle cell carcinoma, fibromatosis and phyllodes tumour of the breast. Histopathology 2008; 52: 45e57. Cohn-Cedermark G, Rutqvist LE, Rosendahl I, Silfversward C. Prognostic factors in cystosarcoma phyllodes. A clinicopathologic study of 77 patients. Cancer 1991; 68: 2017e22. Tavassoli FA, Devilee P, eds. Pathology and genetics of tumours of the breast and female genital tract. Lyon: IARC Press; 2003. 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. 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. Millis RR, Hanby AM, Oberman HA. The Breast. In: Sternberg SS, ed. Diagnostic Surgical Pathology, vol. 1. New York: Raven Press; 1999. p. 319e85.
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FURTHER READING Much of the reference list and a lot of what is outside of it is worthy of reading. in particular two articles by lee et al are recommended as complimentary to this review, with much flesh where i have only supplied bones! Lee AH. Recent developments in the histological diagnosis of spindle cell carcinoma, fibromatosis and phyllodes tumour of the breast. Histopathology 2008; 52: 45e57. 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.
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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. Juvinile fibroadenoma may show marked stromal cellularity and mitotic activity but this is matched by that seen in the epithelial compartment of these lesions
Acknowledgements Drs J St Thomas and G Coast provided helpful comments and illustrative examples.
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Fibroepithelial neoplasms of the breast
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, or even 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 pericanilicular 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). Neither pattern has any particular clinical connotation, although since the intracanilicular pattern is also seen in phyllodes tumours, fibroadenomas with this pattern are those most likely to cause diagnostic difficulty.
Andrew M Hanby
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. What is most important to achieve is the recognition of those lesions in the fibroadenomaephyllodes 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 outgrowth, stromal invasion and both stromal atypia and pleomorphism. These need to be analysed together, not in isolation. Necrosis and heterotypic elements in particular are suggestive of frank malignancy.
Fibroadenoma e epithelial proliferations Fibroadenomas may show a number of epithelial phenomena imposed upon their basic architecture; for example, usual type ductal hyperplasia, sclerosing adenosis, squamous metaplasia and around pregnancy and after lactational change. Additionally there is the ‘complex fibroadenoma’ in which 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 Although some population studies have indicated that there is a modest increase in malignancy following a diagnosis of complex fibroadenoma (3.1 general population) versus a diagnosis of fibroadenoma (1.89 general population),1 the magnitude is
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 phyllodes tumour spectrum. For some malignant phyllodes tumours only a sparse residual epithelial component may remain. The classifications of many of these lesions are morphology based and in many cases the comfort zone provided by pigeonholing entities into specified nomenclature 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 important; phyllodes tumours include some lesions that recur and some lesions that are malignant.
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.
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.
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.
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Figure 2 Complex fibroadenoma. Core biopsy showing early sclerosing adenosis and apocrine metaplasia with cyst formation and occasional calcifications.
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.
such as to have no clinical implications for the individual case and treatment should be as for straightforward fibroadenomas.2 Fibroepithelial neoplasms and particularly phyllodes tumours are more prone to containing co-existing carcinoma, of which in-situ malignancy is most common; both ductal and lobular have been described although lobular carcinoma in situ (LCIS) is most common. 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.
myxoid fibroadenomas are not associated with PPNAD and do not have any harmful associated conditions.
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Mxyoid fibroadenomas may, rarely, be associated with other systemic abnormalities as part of PPNAD.
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Fibroadenomas may show diverse benign epithelial changes. Complex fibroadenomas are associated with in breast cancer risk in large populations but is not enough to have implications for the individual patient. Carcinoma may rarely occur in fibroadenomas
On occasion an otherwise typical fibroadenoma may contain bizarre fibroblasts5,6 (Figure 5). These may be plentiful and unnerving to the unwary. Crucially these rarely have associated stomal mitoses and may also be seen in phyllodes tumours5; such fibroblasts are not associated with any behavioural significance in either fibroadenomas or phyllodes tumours.
Practice point Fibroadenoma e myxoid C
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, more recently encompassed under the title primary pigmented adreonocortical disease (PPNAD) and associated with abnormalities in the PRKAR1A gene.3 This complex also can include cardiac myxomas, cutaneous myxomas and spotty pigmentation,4 as well as other soft tissue tumours and endocrine hyperactivity. In one case known to this author, 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 myxyoid change can be seen within the breast stroma divorced from any defined lesion with characteristics of a fibroadenoma4 (Figure 4) and this change may be more obvious in the interrather than intra-lobular stroma. It should be noted that most
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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 (Figure 6). On occasion these may show infarction and this can be extensive. Whilst in some lesions the vestige of a fibroadenoma of conventional type can suggest a derivation from it, in other cases it is less clear that this lesion is a tumour or merely a dominant lactating lobe.7 These lesions are important in so much as they
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Figure 6 Lactating adenoma. Core biopsy showing infarction with a peripheral subcapsular rim of viable adenomatous tissue. Figure 4 Pattern of mucoid change sometimes seen in primary pigmented adrenocortical disease (PPNAD). 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 PPNAD case.
to include lesions where the glands may not be so well packed and stroma more evident (Figure 7). In any event, these lesions have no harmful implications. Additionally, lesions with hybrid fibroadenoma features are also seen.7
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.
Juvenile fibroadenoma The presentation of these lesions may be alarming with rapid growth and distortion of the breast sometimes seen.8 Such a presentation combined with what can be a very striking histological picture (see below) may suggest a phyllodes tumour 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, however, in juvenile fibroadenoma there is no relative stromal overgrowth, a pericanalicular architecture is seen and increased mitotic activity in the stroma is matched by that seen in the epithelium (Figure 8). Often the epithelium may show a distinct pattern of epithelial proliferation whereby the
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‘Lactating’ adenomas may infarct.
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
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 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.
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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.
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),11 in this author’s experience others look more like fibroadenomas with extensive myoid differentiation (Figure 9).
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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Figure 8
Smooth muscle differentiation may be seen in fibroepithelial neoplasm, some resemble fibroadenomas, others hamartomas
hyperplasia resembles that seen in gynaecomastia.9 This ‘gynaecomastoid hyperplasia’ is distinctive of these lesions. In some rare cases atypical epithelial proliferations are seen.10
Mammary hamartoma and pseudoangiomatous stromal hyperplasia
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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 this author’s 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. 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
Juvenile fibroadenomas show both stromal and epithelial hyperplasia The hyperplasia is typically florid and resembles that seen in gynaecomastia e hence the term gynaecomastoid.
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
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are not the ‘grey’ examples not uncommonly seen in working practice where overlapping features that are open to subjective analysis are seen. 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 epithelialestromal 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,13 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 2, can be detected; 5a in the epithelium and 2 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 c-myc are examples.14 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 can be seen. Thus, the epithelium can influence the stromal growth in this manner. Furthermore, upregulation of insulin-like growth factor 1(IGF1) mRNA can be shown in the stromal components of these, whilst one of its receptors, IGFR1, is expressed on the epithelial cells.15 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 differ in matter of degree without any obvious clear cut-off point. 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 upregulation, and c-myc and EGFR1 amplification16,17 can be demonstrated. Furthermore, there are increasing karyotypic changes.18 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 publications.19,20 Understanding the biology will help in making realistic judgements based on morphology. What follows is a reiteration of standard convention governing these lesions.
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 slitelike 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.
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.12 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 fibroadenomas PASH may be seen in isolation
Phyllodes tumours and the fibroadenomaephyllodes tumour spectrum At the heart of most concerns about fibroepithelial lesions is their distinction from phyllodes tumours. Phyllodes tumours encompass a range of pathologies which can 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, these examples often fall easily into one category or another, and
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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
General clinicopathological features of phyllodes tumours These lesions occur most commonly in the 40e50-year age group.21,22 Although some have noted a lower age incidence in Asian populations, for example 25e30 years in a study by Chua et al,19 in a series of 453 cases from Singapore the mean age was 42 years,17 similar to ‘Western’ populations.
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.
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 mitoses: Fibroadenoma versus benign phyllodes tumours e in general, mitoses are very rare in fibroadenomas and few in number in benign phyllodes tumour, and generally are not the most useful distinguishing feature. However, it should be remembered that mitotic activity within juvenile fibroadenomas may be very high, but this is matched by epithelial mitotic activity which is equivalently high within the context of that lesion (see above).
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 stromalto-epithelial ratio, the interface between the lesion and the normal breast tissue, stromal cellularity, stromal (and epithelial) mitotic activity, stroma 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.23 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.24 The effect of fixation on such features such as mitotic activity should also be considered.
Benign versus borderline versus malignant phyllodes tumours e in this spectrum the number of mitoses increases in the range from benign through to malignant phyllodes tumours. There is variety in the cut 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.25 In the WHO guidelines this is given as ‘few if any’, ‘intermediate’ and ‘numerous (>10 per 10 high-power fields (HPF)).22 This assessment is however context dependent and the view that ‘in the absence of any other worrying features, a mitotic rate of 10 per average (0.44 mm diameter field) 10 HPF’25 is arguably more informative as indicative of malignancy. 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.
Stromal cytology and atypia: Fibroadenoma versus benign phyllodes tumours e in general, the fibroblasts in both these circumstances are relatively bland and nuclear pleomorphism is rarely a criterion used to separate them.
Stromal cellularity: Fibroadenoma versus benign phyllodes tumours e in general, phyllodes tumours are more cellular than fibroadenomas. However, this analysis is subjective20 and some lesions that are fibroadenomas in every other way may have a cellular stroma. More important is the distribution of the cellularity. In typical phyllodes tumours enhanced stromal cellularity is seen immediately beneath the epithelial element (see 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 e with the progression from benign to malignant there is an increase in nuclear pleomorphism, with at the malignant end hyperchromasia and pleomorphism (Figure 11) being more typical of frankly 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.5
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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.
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.
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 e in general, from benign through to malignant there is an increase in stromal cellularity with malignant lesions often very highly cellular (see Figure 11).
Architecture: this is partly a manifestation of the effects of the features additionally described in this section. Classic phyllodes tumours have an intra- rather than a peri-canalicular 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.
Stromal overgrowth: Fibroadenoma versus benign phyllodes tumours e in general, phyllodes tumours have a higher stromal-to-epithelial ratio than fibroadenoma. However, at this end of the spectrum this is very subjective, the ratio varies between different fibroadenomas and on this feature alone the entities merge. Benign versus borderline versus malignant phyllodes tumours e as indicated in the biological overview above, in both fibroadenomas and phyllodes tumours there is a 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 and take on the appearances of a malignant spindle cell neoplasm.
Frank malignancy and heterologous elements in phyllodes tumours Despite the criteria discussed above, the correlation with behaviour is not always good, and most patients will not
Interface between the lesion and the normal breast tissue: Fibroadenoma versus benign phyllodes tumours e 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. Benign versus borderline versus malignant phyllodes tumours e 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
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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.
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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. 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.30,31 Fibroadenoma versus benign phyllodes tumour versus borderline and malignant phyllodes tumour 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.20 Broadly speaking, however, morphology remains the mainstay in assigning a tumour to its position in the fibroadenomaephyllodes spectrum.
Figure 15 Malignant phyllodes tumour. Heterologous osseous focus. Elsewhere in this lesion chondrosarcomatous elements were also found.
experience problems but occasionally apparent low-grade tumours will recur.26 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. 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. Phyllodes tumours can show diverse and often extensive heterologous malignant elements, including osteo-, chondro- and lipo-sarcomatous differentiation (Figure 15).27e29 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.21 Metaplastic carcinoma is outwith 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. Useful markers that will be positive in this regard include CAM5.2, CK5 and CK14.
Periductal stromal tumour This is a rare condition probably related to phyllodes tumours whereby a neoplastic population of stromal cells, similar in cytological characteristics to conventional phyllodes tumours, insinuates itself diffusely around and spreads along mammary ducts, forming a variably cellular cuff. Some variation in nomenclature has occurred in the literature, with the term periductal stromal hyperplasia used in one publication.32 Grossly they may appear multinodular. Burga and Tavassoli encompassed both periductal stromal hyperplasia and sarcoma under the same heading of ‘tumour’ with, at the sarcoma end, three or more mitoses per HPF and stromal nuclear atypia, whilst in the hyperplasias the stroma was bland with only rare mitoses.33 A
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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
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Core biopsy and immunohistochemistry 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
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FURTHER READING Much of the reference list and a lot of what is outside of it is worthy of reading. in particular two articles by lee et al are recommended as complimentary to this review, with much flesh where i have only supplied bones! Lee AH. Recent developments in the histological diagnosis of spindle cell carcinoma, fibromatosis and phyllodes tumour of the breast. Histopathology 2008; 52: 45e57. 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.
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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. Juvinile fibroadenoma may show marked stromal cellularity and mitotic activity but this is matched by that seen in the epithelial compartment of these lesions
Acknowledgements Drs J St Thomas and G Coast provided helpful comments and illustrative examples.
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