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Keywords:

  • breast;
  • diagnosis;
  • fibromatosis;
  • metaplastic carcinoma;
  • needle biopsy;
  • phyllodes tumour;
  • spindle cell carcinoma

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

This article reviews recent advances in the diagnosis of these three unusual tumours of the breast. Spindle cell carcinoma needs to be considered in the differential diagnosis of many mammary spindle cell lesions: it is important to be aware of the wide range of appearances, including the recently described fibromatosis-like variant. Immunohistochemistry using a broad panel of cytokeratin antibodies is needed to exclude spindle cell carcinoma; there is frequent expression of basal cytokeratins and p63. CD34 is often expressed by the stroma of phyllodes tumours, but does not appear to be expressed by spindle cell carcinoma or fibromatosis. Nuclear β-catenin is found in about 80% of fibromatoses, but can also be seen in spindle cell carcinomas and phyllodes tumours. Two recent studies have described features useful in the distinction of phyllodes tumour and fibroadenoma on core biopsy, including increased cellularity, mitoses and overgrowth of the stroma, adipose tissue in the stroma and fragmentation of the biopsy specimen. Periductal stromal tumour is a recently described biphasic tumour composed of spindle cells around open tubules or ducts (but no leaf-like architecture) with frequent CD34 expression. The overlap of morphology with phyllodes tumour suggests that it may be best regarded as a variant of phyllodes tumour.


Abbreviations:
CK

cytokeratin

EGFR

epidermal growth factor receptor

ER

oestrogen receptor

FAP

familial adenomatous polyposis

HPF

high-power fields

PR

progesterone receptor

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

This review discusses the diagnosis of three uncommon tumours of the breast with an emphasis on developments in last few years. In Nottingham each year about two spindle cell carcinomas, one fibromatosis and four phyllodes tumours of the breast are diagnosed compared with about 600 new patients presenting with operable breast cancer.

Spindle cell carcinoma

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

Spindle cell carcinomas represent about 0.3% of all invasive carcinomas of the breast.1 The majority of studies have been based on retrospective series from a single centre; these have the advantage of detailed pathology review, but most are small, with few studies having more than 30 patients.2 There have been some larger series based on consultation cases.

There is a morphological spectrum of carcinomas including a spindle cell component. At one end of the spectrum there is admixed conventional carcinoma; this may be ductal carcinoma in situ or conventional invasive carcinoma, typically of no special type, although other histological types such as invasive lobular carcinoma may be present. There may be transitional zones between the different components of invasive carcinoma.3

A number of recent studies using a variety of genetic methods have shown that the different components of such biphasic carcinomas have a monoclonal origin. For example, identical p53 expression and mutations have been shown in the sarcomatous and carcinomatous components (including carcinoma in situ),4 and identical loss of heterozygosity has been found in the different components.5

In the middle of the spectrum of spindle cell carcinomas there are tumours predominantly composed of spindle cells with small cohesive foci of a few cells, often with a squamoid appearance (Figure 1). These foci can be quite subtle and a careful search is necessary to identify them in some tumours.

image

Figure 1. A, Spindle cell carcinoma predominantly composed of spindle cells with small cohesive focus with squamoid appearance. B, Immunohistochemistry for high-molecular-weight cytokeratins (34βE12) shows expression particularly in the cohesive focus.

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At the other end of the spectrum are carcinomas composed only of spindle cells, which can show a range of pleomorphism. Two recent papers have described tumours composed completely or predominantly of bland spindle cells.6,7 The most important differential diagnosis in such tumours is fibromatosis (Figure 2); occasionally they resemble nodular fasciitis.

image

Figure 2. A, Fibromatosis-like spindle cell carcinoma with minimal nuclear pleomorphism. B, There is expression of cytokeratins (AE1/AE3 antibody). C, CD34 is not expressed in the carcinoma, but there is reactivity of normal vessels and of residual normal stroma around the entrapped gland on the right.

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Other elements may be present in addition to the components described above. The commonest are bone and cartilage, which range from benign to sarcomatous, matrix and osteoclast-like giant cells. Less frequently, other sarcomatous elements, such as rhabdomyosarcoma, are present.

Spindle cell carcinomas can arise in radial scars and papillary lesions8,9 often with fibromatosis-like or low-grade adenosquamous appearance. It is important, when considering this diagnosis, to be aware that scarring with squamous metaplasia can occur after trauma, particularly after core biopsy of a papilloma.

As can be seen from the above descriptions, spindle cell carcinoma of the breast can have a wide range of appearances. It can resemble many other lesions such as pseudoangiomatous stromal hyperplasia. As a result, the diagnosis of spindle cell carcinoma needs to be considered in many spindle cell lesions of the breast. Its diagnosis is relatively straightforward in biphasic lesions. However, a careful search needs to be made for evidence of epithelial differentiation in lesions composed predominantly or purely of spindle cells. First, the tumour must be adequately sampled and a careful search made for ductal carcinoma in situ and cohesive foci of invasive carcinoma. Immunohistochemistry for cytokeratins using a broad panel of antibodies must then be performed.

Immunohistochemistry

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

A number of recent studies have investigated the immunohistochemical profile of spindle cell carcinomas.6,10–13 The majority of tumours show expression of basal cytokeratins [cytokeratin (CK) 5, CK14 and 34βE12] in the spindle cell component. Staining with MNF116 is also frequently positive. Luminal CKs (CAM5.2 and CK7) are expressed in a minority. The broad-spectrum antibody AE1/AE3 is frequently positive in fibromatosis-like spindle cell carcinomas. No CK is expressed in all tumours, so it is important to use a broad panel, including antibodies to both basal and luminal CKs. CKs are often prominent in the small cohesive foci, with less expression in the spindle cells (Figure 1). Provided that the morphology is compatible and that associated ductal carcinoma in situ is present, CK expression in the invasive component is not essential for the diagnosis of spindle cell carcinoma.12

CK immunohistochemistry is very useful, but not every CK+ spindle cell lesion in the breast is a carcinoma. It is important to interpret the results in the light of the histological features, to perform further immunohistochemistry if necessary and not to put too much weight on any individual immunohistochemical result. Malignant melanoma can be composed of spindle cells, is one of the tumours that more often metastasizes to the breast and occasionally expresses CKs, particularly those recognized by the CAM5.2 antibody.14 Leiomyosarcoma can also express CKs; metastasis to the breast appears to be more common than primary mammary tumour. Inflammatory myofibroblastic tumours are very rare in the breast, but can express CKs.15 The key to the diagnosis is the histological appearance: fascicles of fibroblasts/myofibroblasts with prominent chronic inflammation, particularly plasma cells.16 ALK is sometimes expressed. A specialist soft tissue opinion is recommended if the diagnosis of inflammatory myofibroblastic tumour is being considered.

In addition to the frequent expression of basal CKs, there is often expression of other basal or myoepithelial markers such as p63 (Figure 3).11,13 p63 is rarely expressed in conventional mammary carcinoma, occasionally in phyllodes tumours and in mammary sarcomas.11,17,18 p63 and basal CKs are also frequently expressed by squamous cell carcinomas.19 Oestrogen receptor (ER), progesterone receptor (PR) and c-erbB-2/HER-2 are all typically negative in spindle cell carcinomas.1,13,20–22 There is frequent epidermal growth factor receptor (EGFR) overexpression, with amplification in about a third.13,21 The immunohistochemical profile described in this paragraph is similar to the recently recognized basal-like carcinoma of the breast.13,23

image

Figure 3.  Spindle cell carcinoma with (A) strong nuclear expression of p63 (note the staining of myoepithelial cells) and (B) weaker expression of cytokeratins 5 and 6.

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The majority of sarcomas of the breast are components of either a spindle cell carcinoma or a phyllodes tumour. Many older series of mammary sarcoma probably include spindle cell carcinomas, as either no immunohistochemistry was performed or the panel was insufficiently broad.24 The commonest primary sarcoma of the breast is angiosarcoma, and other types are extremely rare. Some will show clear lines of differentiation such as liposarcoma or osteosarcoma. Some undifferentiated mammary sarcomas are morphologically indistinguishable from spindle cell carcinomas and show expression of markers such as p63, CD10 and EGFR, which can also be expressed by spindle cell carcinomas.18 This suggests possible overlap of these two entities, which is supported by CK− spindle cell carcinomas, as discussed above.

CD34 is a useful marker in spindle cell lesions of the breast. It is expressed in normal stroma and frequently in phyllodes tumours, but does not appear to be present in spindle cell carcinomas or fibromatoses (Table 1). The role of β-catenin immunohistochemistry is discussed in the section on fibromatosis below.

Table 1.   Expression of CD34 in spindle cell lesions and spindle cell component of fibroepithelial lesions (based on cases seen by the author including references 10 and 25)
DiagnosisNumberReactivity of spindle cells for CD34
Median % (range)Number with no reactivity (%)Number with <10% reactivity (%)
  1. *Predominant spindle cell component.

  2. †Metastasis to breast.

Fibroadenoma23100 (40–100)00
Phyllodes – all7750 (0–100)4 (5%)8 (10%)
 Benign4670 (10–100)00
 Borderline1250 (0–100)1 (8%)1 (8%)
 Malignant1910 (0–100)3 (16%)7 (37%)
Myofibroblastoma380 (70–95)00
Myoid hamartoma230 (10–50)00
Leiomyoma18000
Pseudoangiomatous hyperplasia6100 (100–100)00
Nodular fasciitis40 (0–0)4 (100%)4 (100%)
Fibromatosis120 (0–0)12 (100%)12 (100%)
Undifferentiated breast sarcoma202 (100%)2 (100%)
Leiomyosarcoma†101 (100%)1 (100%)
Synovial sarcoma101 (100%)1 (100%)
Spindle cell carcinoma*360 (0–0)36 (100%)36 (100%)
Adenosquamous carcinoma30 (0–0)3 (100%)3 (100%)

Lymph node metastases

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

There is evidence that the frequency of nodal metastasis in spindle cell carcinoma is related to differentiation. Wargotz et al. have found that patients with carcinosarcoma, defined as containing cellular mitotically active pleomorphic spindle cells resembling sarcoma in more than half the tumour in association with conventional carcinoma, had nodal metastases in 26%.3 The same group have found that patients with spindle cell carcinoma, defined as a containing a bland spindle cell proliferation in more than half the tumour, had nodal metastases in 6%.20 The two recent studies of fibromatosis-like spindle cell carcinoma have found that all were node-negative. 6,7 There is some evidence that risk of nodal metastasis is related to the extent of the epithelial component in the primary tumour. Nevertheless, nodal metastases can be seen in pure spindle cell carcinomas.1

It is difficult to make a reliable estimate of the frequency of nodal metastases, as most unselected series have small numbers and not all patients have axillary surgery. Nevertheless, the overall frequency does appear to be less than conventional mammary carcinoma.2 It is reasonable to suggest that for most patients it would be appropriate to perform sentinel node biopsy or axillary node sample rather than axillary clearance. It may be possible to avoid axillary surgery in patients with fibromatosis-like spindle cell carcinoma.6,7 Another approach would be to ultrasound the axilla and perform core biopsy of abnormal nodes.26

Survival

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

Definitive comment about the prognosis of spindle cell carcinoma is not possible, because most of the series are small and the selection criteria not consistent.

There is evidence that prognosis is related to differentiation. Wargotz et al. have found that patients with carcinosarcoma, defined as containing cellular, mitotically active pleomorphic spindle cells resembling sarcoma in more than half the tumour, had a 5-year survival of 49%.3 The same group have found that patients with spindle cell carcinoma, defined as a containing a bland spindle cell proliferation in more than half the tumour, had a 5-year survival of 64%.20 The two recent studies of fibromatosis-like spindle cell carcinoma have found that only occasional patients had distant metastases and died of disease, although the length of follow-up was short.6,7 The majority of studies suggest that the overall prognosis for this group of tumours is poor compared with conventional invasive mammary carcinoma;1,2 this apparent discrepancy between these studies and the studies of different subtypes is probably because most tumours are poorly differentiated.

The commonest sites of distant metastases of spindle cell carcinoma are the lung and bone,1,12 also common sites of metastases for conventional mammary carcinoma. It has been argued that spindle cell carcinomas with only focal conventional carcinoma should be managed as sarcomas because of the low frequency of nodal involvement and high frequency of local recurrence and distant metastasis. This is a reasonable hypothesis, but there do not appear to be any randomized trials of different treatments. Such trials are needed. It is important to achieve complete local excision, including of the fibromatosis-like variant.6,7 The typical absence of expression of ER, PR and HER-2 limits the treatment options.

Fibromatosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

Fibromatosis is rare, but well recognized in the breast.27–29 It is seen over a wide age range and is much more common in women. It typically presents as a breast mass, and the clinical and mammographic appearances frequently suggest carcinoma. It may arise within the breast, but often appears to arise from the deep fascia. It is possible that trauma may have a role in the pathogenesis of some cases.

The assessment of the excision margins in surgical specimens is important, because if excision is incomplete there is a high risk of recurrence. Recurrence is often within the first 3 years. Fibromatosis of the breast occasionally invades deep into the chest wall. Preoperative diagnosis is valuable because it enables definitive surgery to be planned. This increases the chance of complete excision at the first attempt. It is important not to overinterpret the changes seen in a needle core biopsy specimen: it is not always be possible to make a definite diagnosis.

Until recently the diagnosis of fibromatosis was largely based on the histological features seen in haematoxylin and eosin sections. It is composed of fascicles of spindle cells with usually minimal pleomorphism and few or no mitoses. The degree of cellularity can be variable, with some tumours containing very collagenous areas. The margin is infiltrative and the tumour may invade around normal structures. Lymphocytes are often seen at the edge.

The differential diagnosis includes scarring—useful clues are evidence of fat necrosis and haemosiderin-laden macrophages. Spindle cell carcinoma must be excluded by looking for cohesive foci and ductal carcinoma in situ, and performing immunohistochemistry with a panel of antibodies to CKs. Nodular fasciitis typically presents as a rapidly enlarging, tender, subcutaneous mass and usually contains loose myxoid stroma and haemorrhage. Occasionally, fibromatosis of the breast may show overlap of features with nodular fasciitis.16 The opinion of a specialist soft tissue pathologist is useful in such cases.

Immunohistochemistry

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

Fibromatosis often expresses actin, and occasionally desmin and S100.10,16 CKs are not expressed, in contrast to spindle cell carcinoma. CD34 is also negative, but it is important to assess immunoreactivity away from entrapped glands, which may have residual normal stroma around them (Figure 2C).

Fibromatosis may be seen in patients with familial adenomatous polyposis (FAP), which is the result of germ-line mutations in the adenomatous polyposis coli gene, whose protein regulates β-catenin. Nuclear β-catenin expression is described in 80% of fibromatoses of the breast (Figure 4).30 Alteration in the β-catenin or FAP gene is frequently seen, as in desmoid tumours, but in contrast to superficial fibromatoses, which do not show such changes.

image

Figure 4. A, Fibromatosis with involvement of skeletal muscle. B, There is nuclear expression of β-catenin by the fibromatosis, but not by the inflammatory cells.

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Fibroadenomas and phyllodes tumours may also show nuclear β-catenin expression, but the mechanism appears to be different.31,32 Nuclear β-catenin expression can be seen in a small proportion of spindle cell carcinomas (Figure 5, J Reis-Filho et al. unpublished data), but does not appear to be present in scars. Interpretation of β-catenin immunohistochemistry can be difficult, as sometimes the reactivity is strong, which hampers assessment of whether it is nuclear or just cytoplasmic.

image

Figure 5.  Spindle cell carcinoma with (A) cytokeratin expression particularly in the more cohesive areas (CAM5.2 antibody) and (B) nuclear expression of β-catenin. The endothelial cells show cytoplasmic, but not nuclear immunoreactivity.

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Phyllodes tumour

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

Phyllodes tumour is an uncommon fibroepithelial lesion of the breast. It needs to be distinguished from fibroadenoma, which is about 50 times more common. The distinction of malignant phyllodes tumour from fibroadenoma is straightforward. Malignant phyllodes tumours typically show stromal pleomorphism, with overgrowth and mitoses and infiltrative margins. However, there is no clearly defined cut-off between benign phyllodes tumour and fibroadenoma, making the distinction much more difficult. Benign phyllodes tumours, like fibroadenomas, usually have a circumscribed edge, the stromal cells do not show marked pleomorphism and there are usually few mitoses. A leaf-like pattern is nearly always present, but can also be seen in fibroadenoma. Thus the most important feature is stromal cellularity, which is rather subjective.

Needle core biopsy diagnosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

The preoperative diagnosis of fibroepithelial lesions is important, because fibroadenomas are often not removed, whereas phyllodes tumours are excised because of the risk of local recurrence and occasionally distant metastasis. The triple approach using cytology in addition to clinical and radiological features may give disappointing results.33 Fine-needle aspiration cytology is sometimes helpful in suggesting the diagnosis of phyllodes tumour if it is borderline or malignant, but the distinction between benign phyllodes tumours and fibroadenomas is often difficult.34,35 This distinction should potentially be easier in needle core biopsies, because of the extra architectural information provided by histology compared with cytology.

A number of recent studies have looked at the core biopsy diagnosis of phyllodes tumours. There have been two approaches. One has been to study the excision findings of lesions reported on core biopsy as fibroepithelial lesion with cellular stroma: the proportion which were phyllodes tumours varied from 29% to 72%.36–39 The largest of these studies, by Komenaka et al., has described 57 core biopsies in which the histological features raised the possibility of phyllodes tumour. The final excision specimen diagnosis was phyllodes tumours in 19 of 23 in which the core favoured phyllodes tumour, four of nine cores with equivocal features and two of 25 in which the core favoured fibroadenoma. These results suggest that it is possible to stratify the risk of phyllodes on core biopsy features. However, a major weakness of this study is that no criteria have been given for these three diagnostic categories.

The other approach was to start with the excision diagnosis and then look at the previous core biopsies. One study was a detailed review of histological features.39 Two studies have also looked at the histological diagnosis and radiological features.33,38

Two papers, one from each of the above groups, have looked at the histological features useful in distinguishing phyllodes tumour and fibroadenoma on core biopsy. One, from Boston, has studied 29 core biopsy specimens showing a fibroepithelial lesion with cellular stroma on core.37 The other, from Nottingham, started with consecutive series of 36 phyllodes tumours and 38 fibroadenomas categorized on the excision specimen diagnosis and then studied the corresponding core biopsy specimens.39

As one would expect, stromal cellularity was higher in cores from phyllodes tumours than from fibroadenomas in both studies. We found that increased stromal cellularity compared with a typical fibroadenoma in at least half the core was a useful cut-off (Figure 6A).39 The Boston study had a lower threshold and, as a result, a higher proportion of their cases were fibroadenoma on excision.37

image

Figure 6.  Needle core biopsy specimens of phyllodes tumour showing (A) increased stromal cellularity, (B) fragmentation and (C) adipose tissue within stroma.

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Stromal overgrowth, defined as a ×10 field with no epithelium, was much more common in cores of phyllodes tumours.39 The Boston study did not find this feature useful, but used a lower magnification, so this feature was rarely found to be present.37 Other methods of assessing this feature are to estimate the ratio of stroma to epithelium or the proportion of stroma, but these are more subjective and selection of a cut-off is difficult.

Both studies have found that an intracanalicular growth pattern and clefting are not useful discriminants of the two diagnoses. Fragmentation, defined as stroma with epithelium at one or both ends of the fragment (Figure 6B), is present in about a third of cores of phyllodes tumours and rarely seen in fibroadenomas.39 Fragmentation is probably the result of the core sample being taken across a leaf-like part of the tumour.

Marked stromal pleomorphism and atypical heterologous elements are seen only in malignant phyllodes tumour, and biopsy specimens with these histological changes usually also have other features to support the diagnosis of phyllodes tumour. Stromal pleomorphism is of little value in distinguishing between benign phyllodes and fibroadenoma, as moderate pleomorphism is not uncommon on fibroadenomas.

Stromal mitoses are seen in between one-third and three-quarters of phyllodes tumours.37,39 They are seen in a minority of cores from fibroadenomas and usually the count is only one or two mitoses per 10 high-power fields (HPF). This suggests that a count above two mitoses per 10 HPF favours phyllodes tumour, but there are problems of reproducibility of assessment.39 Ki67 counts in the stroma of phyllodes tumours are significantly higher than in fibroadenomas in both core biopsy37 and surgical specimens,40,41 but there is a large degree of overlap, so Ki67 counts add little to mitotic counts.

An infiltrative margin favours phyllodes tumour, but, surprisingly, the Boston study found this in 36% of fibroadenomas and the Nottingham study found poor interobserver reproducibility. The presence of adipose tissue in the stroma of a fibroepithelial lesion may be because it is an intrinsic part of the lesion or reflect invasion into adjacent fat. Adipose tissue within stroma is present in about a third of cores of phyllodes tumours (Figure 6C).39 It may also be present in hamartomas, but is rarely seen in a fibroadenoma.

Most of the features described above are not completely specific for phyllodes tumour or fibroadenoma. It is therefore best not to rely too much on any individual feature, but to use them in combination. Further studies on how to use the histological features discussed above in combination would be useful, ideally in prospective series. It is sometimes possible to make a definite diagnosis of phyllodes tumour, but often the conclusion is ‘phyllodes tumour cannot be excluded’.

An important conclusion from these recent studies is that about 25–30% of core biopsy specimens from lesions that are later found to be phyllodes tumours are false negative, i.e. there are no features raising the possibility of this diagnosis.33,38,39 Occasionally the most likely explanation is that the core biopsy has missed the lesion.38 The usual reason is tumour heterogeneity: parts of the tumour have features of phyllodes tumour and parts have features of fibroadenoma.39 Occasionally, the phyllodes tumour may be arising in a fibroadenoma.33,39 One study has suggested that false-negative results are more likely in larger tumours.33

When reporting fibroepithelial lesions on core biopsy a balance has to made between the sensitivity of diagnosis of phyllodes tumour and having too low a threshold for reporting minor changes, thus excising too many fibroadenomas. It is important to be aware that a diagnosis of fibroadenoma on core biopsy does not completely exclude phyllodes tumour, but the risk is <1%.39

An important way to reduce the impact of false-negative core biopsy diagnoses is to include clinical and radiological features in the decision about whether to excise the lesion. If the tumour is growing in size, or is >30 mm, then excision should be suggested.33,38,39 Age is not of value in the decision. Although the average age of women with phyllodes is higher than for women with fibroadenoma, because fibroadenoma is much commoner, the great majority of fibroepithelial lesions in older women are fibroadenoma.39 Also, phyllodes tumours are well recognized in women <20 years old.42 Radiology is of limited value in distinguishing between phyllodes tumours and fibroadenomas, as there is a large overlap of features.43,44 Excision should be considered if septae are seen on ultrasonography.45

Biology

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

The conventional view is that fibroadenomas are polyclonal proliferations of the stroma and phyllodes tumours are monoclonal neoplasms of the stroma, with polyclonal epithelium in both.46 Recent evidence has challenged this view. A study of three patients with fibroadenomas, who then developed phyllodes tumours at the same site, has shown that the fibroadenomas and subsequent phyllodes were monoclonal, with both lesions in one patient showing the same monoclonality (inactivation of the same allele on the X chromosome).47 Areas of stromal overgrowth in fibroadenomas can also be monoclonal.48 Allelic imbalance and monoclonality can occur in the epithelium as well as the stroma of phyllodes tumours.48,49 Epithelial expression of ER and PR in phyllodes tumours is inversely related to grade, suggesting interactions between the stroma and epithelium.50 These results raise interesting questions about the recently described phyllodes tumour with metastasis of both epithelial and stromal components.51

A recent study from the Institut Curie has found that borderline and malignant phyllodes tumours had significantly more chromosomal changes (mean of six) than benign phyllodes tumours (mean of one).52 This suggests that there may be an important biological cut-off between borderline and benign phyllodes tumours. Gain of chromosome 1q is a common change in phyllodes tumours.52,53

Stromal p53 protein expression is seen particularly in malignant phyllodes tumours,54,55 and there is evidence that malignant phyllodes tumour is found at increased frequency in families with the Li-Fraumini syndrome, in which there are germ-line p53 mutations.56 Expression of c-kit is also seen, particularly in malignant phyllodes tumours, but there are no kit activating mutations, in contrast to gastrointestinal stromal tumours, which usually express c-kit and have activating mutations.55,57,58 EGFR expression and mutations are seen in stromal cells, especially in malignant phyllodes tumours.59 These results also emphasize the biological differences with grade.

The distinction of benign phyllodes tumour from fibroadenoma is based on morphology. Immunohistochemistry is sometimes of value at the more malignant end of the spectrum if the appearance is not typical of phyllodes tumour, e.g. if the epithelial architecture is not typical or there is no epithelium particularly in a core biopsy specimen (Figure 7). CKs are useful in distinguishing from spindle cell carcinoma.10 CD34 expression supports the diagnosis of phyllodes tumour (Table 1, Figure 7).

image

Figure 7. A, Core biopsy specimen of malignant phyllodes tumour composed of sheets of pleomorphic cells with no epithelium and (B) CD34 expression. There is no expression of cytokeratins. C, The surgical specimen shows more typical phyllodes tumour architecture.

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β-Catenin is frequently expressed in stromal cell nuclei in phyllodes tumours, particularly of low grade,31 but mutations are not found in the β-catenin gene and very rarely in the adenomatous polyposis coli gene, in contrast to fibromatosis. There is evidence that other factors may be important in stromal expression of β-catenin: epithelial overexpression of Wnt5a, stromal overexpression of Wnt2 31 and stromal expression of insulin-like growth factors.32

Prognostic features

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

There are widely accepted prognostic and predictive factors for invasive carcinomas of the breast, including an internationally recognized system of histological grading.60 Treatment can be guided by large randomized, controlled trials. By contrast, there are much less data for phyllodes tumour, which is about 100 times less common. There is much less consensus on the relationship of pathological features to clinical behaviour, and there do not appear to be prospective randomized studies of treatment.

A major difficulty with the data on prognostic factors in phyllodes tumours is that studies are retrospective and treatment is not standardized. There is evidence of selection bias for the type of surgery, with malignant and larger tumours more likely to have extensive surgery. Most series are from a single centre, with few having more than 100 patients.

Local recurrence

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

Most series have described an association between tumour at the margin and local recurrence.61–65 Low local recurrence rates can be achieved with complete excision.66,67 There is evidence that local recurrence is related to the extent of surgery, but this is based on retrospective non-randomized studies.68 However, recurrence is not inevitable if margins are involved.62 Some series have suggested that local recurrence is more frequent in higher grade phyllodes tumours.68 Tumour size is a possible risk factor for local recurrence.62,69 Recurrent disease is most often of similar grade to the original in the majority, but sometimes is of higher grade and occasionally lower.64

From a practical point of view, the major determinant of local recurrence appears to be completeness of excision. If a diagnosis of phyllodes tumour is made on needle core biopsy, then excision with a rim of normal tissue should be recommended. Unfortunately, there do not appear to be studies relating the distance from the tumour to the margin and the risk of local recurrence; prospective studies are needed to address this issue. Some authors have suggested that if an incompletely excised benign phyllodes tumour is diagnosed unexpectedly on excision, that further surgery may not be essential and a ‘wait and see’ policy may be appropriate.70 Trials of extent of surgery in this group of patients and those that are at the border between fibroadenomas and phyllodes tumour would be useful.

Distant metastasis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

Distant metastases are seen in <10% of patients with phyllodes tumour, with lungs, pleura and bone the commonest sites.63–69,71 Typically, metastases are composed of the sarcomatous stromal component,64 but a recent case report has described pulmonary metastases with epithelium surrounded by myoepithelium as well the sarcomatous component.51 There are conflicting results on the relationship between local recurrence and distant metastases, with some finding a high frequency of local recurrence before distant metastases.69 Nodal metastases are rare, even in malignant phyllodes tumours, so there is no need for routine axillary surgery.66,69,72,73

The majority of studies have found a clear relationship between histological grade and distant metastasis, with most distant metastases being from malignant tumours.64,71 The following features are considered in most grading systems: cellularity, pleomorphism, mitotic count and overgrowth of the stroma and whether the margin is infiltrative. There is a strong correlation between these different features. A range of heterologous components can be seen, including adipose, chondroid and osteoid elements and rhabdomyosarcoma.64 Some studies have suggested that such heterologous elements are present only in malignant phyllodes tumours.61 This is true for the majority of phyllodes tumours, and clearly, if the heterologous component is sarcomatous, the tumour must be regarded as malignant, but some elements such as benign adipose and chondroid tissue can be seen in benign and borderline tumours.64,74 There are differing views on which histological features are most important in assessing behaviour,66,67,73 and as a consequence there is wide variation in the proportion of different grades (2–45% are categorized as malignant in larger series71). Standardization of grading, as with invasive mammary carcinoma, is unlikely to occur until it is an important factor in decisions about treatment.

Periductal stromal tumour

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References

Periductal stromal tumour is a recently proposed entity described by Burga and Tavassoli.75 It is a biphasic tumour of the breast predominantly composed of spindle cells that are situated around open tubules or ducts. Typically, there are multiple nodules with intervening adipose tissue. The nodules often have an infiltrating margin. There is no phyllodes leaf-like architecture. There is a range of stromal pleomorphism and mitoses used to categorize the lesions as periductal stromal hyperplasia or periductal stromal sarcoma. The illustrations in the study suggest that the stromal cellularity of periductal stromal sarcomas is like phyllodes tumour. There are no illustrations of periductal stromal hyperplasia, no description of the degree of stromal cellularity and scarcely any comment in the discussion of the paper.

This is a rare pattern of mammary tumour. There is overlap of morphology with phyllodes tumour (Figure 8) and one lesion recurred as typical phyllodes with a leaf-like architecture. Also, there is frequent expression of CD34 as in phyllodes tumour. The description of periductal stromal sarcoma is useful, as it enables this pattern to be recognized, but it may be better to regard periductal stromal sarcoma as a variant of phyllodes tumour rather than as a distinct entity. The recommended management of complete excision is the same for both. The description of periductal stromal hyperplasia is insufficiently detailed for reliable comment.

image

Figure 8. A, Phyllodes tumour composed of islands of spindle cells around a duct with intervening adipose tissue. There is a slight leaf-like architecture, but the appearances are similar to the description of periductal stromal sarcoma. B, There is increased stromal cellularity and atypia.

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References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Spindle cell carcinoma
  5. Immunohistochemistry
  6. Lymph node metastases
  7. Survival
  8. Fibromatosis
  9. Immunohistochemistry
  10. Phyllodes tumour
  11. Needle core biopsy diagnosis
  12. Biology
  13. Prognostic features
  14. Local recurrence
  15. Distant metastasis
  16. Periductal stromal tumour
  17. Acknowledgement
  18. References
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