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This study aims to review histological and immunohistochemical features that are useful in the diagnosis of metastases to the breast. Histological features were compared between non‐haematological metastases to the breast and 100 consecutive core biopsy specimens of primary invasive carcinomas of the breast. 18 non‐haematological metastases to the breast were diagnosed over a 10‐year period (0.3% of malignant mammary tumours). Elastosis and carcinoma in situ were seen only in primary mammary cancers. Two‐thirds of tumours had features raising the possibility of metastasis, such as clear cell carcinoma suggestive of renal origin and small cell carcinoma suggestive of pulmonary origin. The features observed in haematological metastases are also described. Immunohistochemical panels to distinguish mammary carcinoma (oestrogen receptor, gross cystic fluid protein‐15) from common metastases to the breast, including carcinoma of the lung (thyroid transcription factor‐1), malignant melanoma (S100, HMB45, melan‐A) and ovarian serous papillary carcinoma (Wilms' tumour 1), are discussed. The pathologist has a key role in considering the diagnosis of metastasis to the breast if the histological features are unusual for a primary mammary tumour. The clinical history is vital in some cases. Immunohistochemistry plays a useful supplementary role.
The diagnosis of metastases to the breast from extramammary malignancies, and distinction from primary mammary malignancy, is important for patient management. The prognosis is generally poor as most patients have widely disseminated disease.1,2,3 Most patients die within a year of diagnosis,2,4,5,6,7 although longer survival is well recognised if there is effective systemic treatment.2,6 In many patients, systemic treatment or palliative care is more appropriate than extensive surgery. Accurate diagnosis can therefore prevent unnecessary surgery.
The aim of this paper is to describe histological and immunohistochemical features that are useful in the diagnosis of the common tumour types that metastasise to the breast. There is increasing use of needle‐core biopsy rather than fine‐needle aspiration cytology in non‐operative diagnosis of breast disease. The emphasis in this article is on the diagnosis in needle‐core biopsy: if a diagnosis can be made at this stage then appropriate management can be planned.
The most common metastatic tumours in the breast are from mammary primaries,8,9 but these are excluded in most series and will not be discussed here. A wide range of extramammary tumours have been described as metastasising to the breast, the largest group being haematological malignancies. Other common types are carcinoma of the lung, malignant melanoma, serous papillary carcinoma of the ovary, carcinoma of the prostate, kidney and stomach, and carcinoid tumours.10 Malignant tumours of the breast are rare in people aged <20 years. In this small group, metastases to the breast outnumber primary tumours, and the most common tumours metastasising to the breast are rhabdomyosarcomas and lymphomas.11,12 Metastases to the breast are much more common in women.9
The frequency of metastastic tumour in the breast from extramammary malignancy compared with primary mammary carcinoma, based on histological diagnosis in clinical studies, varies between 0.2% and 1.3%.4,5,7 Higher frequencies of 2–7% are seen in postmortem studies.8,13 In approximately 30% of patients, the metastasis to the breast is the first sign of malignancy.1,4,5,6,7,9 In those with a history of malignancy, the time from initial diagnosis to metastasis to the breast varies between 1 month and 15 years, with averages between 1 and 5 years.1,2,5,14,15,16 A long interval is well recognised for some tumour types such as malignant melanoma and ovarian carcinoma (table 11).5
Patients typically present with a rapidly growing painless firm palpable breast mass.1,2,7,14,15,16,17 Some reports emphasise that the masses are often superficial,4,18 but usually they are not tethered to the skin.14,15,17 Diffuse skin involvement is rare.
The most common mammographic appearance is of a rounded mass with well‐defined or slightly irregular margins.7,15,18,19 Multiple or bilateral tumours are seen in a minority. Calcification is rare, apart from metastases from ovarian serous papillary carcinomas.1,6,20 Spiculation is uncommon in contrast with primary mammary carcinomas.15,20 Ultrasound scan typically shows a hypoechoic mass, which is sometimes heterogeneous or poorly defined.18 Axillary lymphadenopathy is sometimes apparent.
The histological features in 18 non‐haematological metastases to the breast seen over a 10‐year period (1996–2005) were compared with a nearly consecutive series of 100 core biopsy specimens in 2006, showing invasive carcinoma with later surgical excision (table 22),), and larger series of core biopsy21 and excision specimens.22
Often metastases to the breast show histological features, such as clear cell carcinoma suggestive of renal origin, which are not typical of primary carcinoma of the breast (table 11).). The clues can sometimes be subtle such as pigment and intranuclear inclusions in malignant melanoma. In our experience, about a third of lesions do not show specific histological features (table 11).). For example, large cell carcinoma of the lung may resemble grade 3 invasive ductal carcinoma of the breast. A history is often essential to make a correct diagnosis in such patients.
Elastosis is common in primary mammary carcinomas, but rare in extramammary tumours (table 22).). The presence of carcinoma in situ strongly supports the diagnosis of primary carcinoma (table 22),), but can be very rarely seen in association with metastasis from an extramammary primary carcinoma.23 Calcification is common in mammary carcinomas, but is rarely seen in metastases to the breast with the exception of serous papillary carcinoma of the ovary or peritoneum (table 22).
Four growth patterns of metastases to the breast are described. The most common one is a circumscribed nodule with surrounding normal breast tissue.5,7 Infiltration around ducts and lobules is particularly associated with lymphomas, leukaemias and malignant melanoma.1,2,13,16 This pattern has been suggested to be a clue to the diagnosis of metastasis to the breast, but it can be seen in primary breast tumours. It was only apparent in haematological malignancies in the tumours from Nottingham City Hospital. Lymphangitis and diffuse infiltration are less‐common patterns. These growth patterns are less easy to appreciate in a core biopsy than in surgical specimens.
The most useful data in making the diagnosis of metastasis to the breast are the clinical history and morphological assessment of haematoxylin and eosin (H&E)‐stained sections, particularly if sections of the primary tumour are available for comparison. When considering a possible diagnosis of metastasis to the breast from a known malignancy elsewhere, it is important to ask oneself whether the extramammary tumour may in fact be a metastasis from the breast tumour. If there is no history, immunohistochemical analysis may be helpful in supporting origin from an extramammary site. An immunohistochemical comparison with a known extramammary primary tumour using a panel of antibodies may be useful in small biopsies with limited tissue for assessment or tumours without distinctive histology, which could be either a primary mammary tumour or metastasis from an extramammary malignancy.
When performing immunohistochemical analysis it is important to remember that no marker is 100% specific or sensitive. Thus, one should use panels of antibodies and not rely too much on any individual result. There is a danger of false‐negative results in small biopsies, particularly if the antigen is only focally present. Also, metastases sometimes show a different immunophenotype from the primary tumour, but usually for just one or two markers. Important contributory factors to the percentage of positive results for each antibody discussed below are technical details (fixation, processing, pretreatment and immunohistochemical method), criteria for a positive result and selection of tumours. The percentage of tumours described as expressing different markers in the sections below must therefore be regarded as approximate. The choice of antibodies used should be based on the history and morphology of the tumour.
The combination of cytokeratin 7 and cytokeratin 20 is useful in categorising carcinomas (table 33).24,25 Breast cancer, including the common special types, is typically cytokeratin 7+ and cytokeratin 20−.26 Almost all breast cancers stain with the cytokeratin antibody CAM5.2 and are positive for epithelial membrane antigen.27,28 S100 is expressed in 50%29,30 and carcinoembryonic antigen in 30% of mammary carcinomas.31 Oestrogen receptor is expressed in 80% and progesterone receptor in 60% of mammary carcinomas,32,33,34 with most tumours being either clearly positive or completely negative.34 Convincing expression of oestrogen receptor is largely restricted to carcinomas of the breast, endometrium and ovary.35 Occasionally, tumours from other sites express oestrogen receptor, but usually it is weak and focal.35,36,37 Gross cystic disease fluid protein‐15 (GCDFP‐15) is often expressed by carcinomas of the breast (70%), salivary glands and skin appendages and occasionally by other carcinomas.36,38,39
Serous papillary carcinoma is the most common type of ovarian tumour to the metastasise to the breast and can also involve axillary lymph nodes.40 Histologically, it is not possible to distinguish it from serous papillary carcinoma of the peritoneum, which can also spread to the breast. Usually, the papillary architecture is apparent, but sometimes there may be just a solid growth pattern making diagnosis more difficult. Occasionally, the time from initial diagnosis of ovarian primary to mammary metastasis is several years. The histological clue to the diagnosis is that the papillary architecture is not a typical pattern for most histological types of invasive carcinoma of the breast (fig 1A,B1A,B).). Serous papillary carcinoma can resemble invasive micropapillary carcinoma of the breast and calcification can be seen in both.
Both mammary and non‐mucinous ovarian carcinomas are typically cytokeratin 7+, cytokeratin 20− and often positive for oestrogen receptor. The pattern of epithelial membrane antigen expression is useful: invasive micropapillary carcinoma has expression on the outside of the papillary clusters, but not around the central spaces, whereas serous papillary carcinoma has expression on both surfaces (fig 1G,H1G,H).
Nuclear expression of Wilms' tumour 1 is present in about 70% of ovarian carcinomas and in 95% of serous papillary carcinomas (fig 1D1D),), but is present in <10% of breast cancers (although there do not seem to be any data for invasive micropapillary carcinoma).41,42,43,44 It is also present in other tumours such as mesothelioma.45
GCDFP‐15 is present in about 70% of breast cancers, including invasive micropapillary carcinomas,46 and rarely seen in ovarian carcinoma.35,36,38,39,44 Thus, expression of this marker favours breast cancer and the absence of staining is not helpful.
Staining for Ca125 is seen in about 60% of ovarian carcinomas and in 90% of serous papillary carcinomas (fig 1F1F).). It is also commonly seen in endometrial, endocervical, biliary and pancreatic carcinomas, but infrequently in breast cancer (10–20%).35,39,44,47
Mesothelin is often expressed in carcinomas of the ovary (over 90% of serous papillary carcinomas), prostate and mesotheliomas and weakly expressed in 3–14% of breast cancers.35,48,49 Intermediate levels of staining are seen in adenocarcinomas of the lung, stomach and colorectum.
The histological appearance of malignant melanoma can be varied, including epithelioid, spindle and plasmacytoid cells, and may overlap with mammary carcinoma (table 11).50 Useful clues to the diagnosis are cytoplasmic pigment, intranuclear inclusions and spindle cells (fig 2A,B2A,B).
S100 is the most sensitive immunohistochemical marker of melanoma (expressed in about 95%, fig 2C2C).). However, it is not specific, being present in many other tumours, including about 50% of breast cancers,29,30 and must therefore be used in combination with other markers. A panel of cytokeratins is useful to exclude carcinoma (fig 2D2D).). HMB45, melan‐A, microphthalmia transcription factor and tyrosinase are all less sensitive, being present in about 70% of melanomas, and more specific than S100.51,52,53 Melanoma can show aberrant expression of cytokeratins, particularly with CAM5.2, epithelial membrane antigen, CD38 and CD68.50
The major clue to the diagnosis of oat cell carcinoma is the appearance on H&E‐stained sections. It is typically composed of sheets of cells with speckled chromatin without prominent nucleoli, scant cytoplasm, necrosis, frequent mitoses and crush artefact (fig 3A3A).). Immunohistochemistry is useful to confirm the diagnosis. Membranous staining for CD56 is present in 95% (fig 3B3B)) and other neuroendocrine markers, such as synaptophysin and chromogranin A, are less frequently seen.54 There is typically dot positivity with CAM5.2. Thyroid transcription factor‐1 (TTF‐1) is present in about 80% of both pulmonary and non‐pulmonary small cell carcinomas (and can be seen in primary mammary small cell carcinoma).55,56 The possibility of metastasis, particularly from the lung, should be considered if small cell carcinoma is diagnosed in the breast, as primary mammary small cell carcinoma is very rare.57 The presence of ductal carcinoma in situ or in oestrogen receptor favours the diagnosis of primary mammary small cell carcinoma.56,57
Pulmonary adenocarcinomas may have morphological clues such as an acinar growth pattern or mucin‐secreting columnar cells (fig 3C3C).). TTF‐1 is expressed by about 75% of pulmonary adenocarcinomas (fig 3D3D)) and, apart from carcinomas of the lung and thyroid, it is rarely seen in other carcinomas.35,45,55,58 TTF‐1‐positive conventional mammary carcinoma can rarely be seen (Colin Purdie, personal communication). Expression of oestrogen receptor and GCDFP‐15 favour a primary breast carcinoma although convincing expression is seen occasionally in pulmonary adenocarcinomas.35,36,37
Primary keratinising squamous carcinoma of the breast is very rare, so metastasis, particularly from the lung, needs to be considered with this histological appearance. The recently recognised basal carcinoma of the breast can show squamoid differentiation without keratinisation59,60—such tumours are typically grade 3, express basal keratins such as cytokeratin 14 and are often negative for oestrogen receptor, progesterone receptor and HER‐2.61 TTF‐1 is rarely, if ever, present in pulmonary squamous carcinoma.58 Owing to this overlap in morphology and immunophenotype, the clinical history may be essential for making the correct diagnosis of metastasis from extramammary non‐keratinising squamous carcinoma (fig 3E3E).
Metastasis from large cell carcinoma of the lung and poorly differentiated breast cancer are difficult to distinguish on H&E‐ stained sections (fig 3F3F).). Some large cell carcinomas of the lung express TTF‐1.62 Expression of oestrogen receptor and GCDFP‐15 favours breast cancer. Clinical history and comparison with previous histology may be needed to make an accurate diagnosis.
The morphology of prostatic carcinoma overlaps with mammary carcinoma (fig 44,, table 11).). Prostatic carcinoma may have columnar cells and even if the nuclei are relatively bland they typically contain a nucleolus. Prostate‐specific antigen and prostatic acid phosphatase are excellent markers of prostatic carcinoma as both are expressed in nearly 100% of tumours (fig 44).35,63,64,65 Apart from tumours of the salivary gland,66,67 few other tumours express these markers. Recent reports suggest that male breast cancers can express prostate‐specific antigen (15%) but not prostatic acid phosphatase.68,69,70 Oestrogen receptor, GCDFP‐15 and cytokeratin 7 are uncommon in prostatic carcinoma,35,65 so expression of these markers favours breast cancer.
The intestinal pattern of gastric carcinoma may resemble invasive ductal carcinoma of the breast, and diffuse gastric carcinoma may resemble invasive lobular carcinoma of the breast (fig 55).). Columnar mucin‐secreting cells favour gastrointestinal origin. Some earlier reports describe oestrogen‐receptor‐positive gastric carcinoma, but recent studies suggest that this is rare.35,71,72,73 Oestrogen receptor is expressed by 95% of invasive lobular carcinomas,32,34 so this marker is particularly useful in the distinction from diffuse gastric carcinoma. Several recent studies did not find GCDFP‐15‐positive stomach cancer.35,71,73 CDX2 is present in between 20% and 70% of gastric carcinomas but not in breast cancer.35,73,74,75 Cytokeratin 20 is more often present in gastric carcinoma (50%) than in mammary carcinoma.
Conventional renal cell carcinoma is the most common renal malignancy and the most likely to metastasise to a wide range of sites76 including the breast. The abundant clear or granular cytoplasm with prominent fine vessels are useful clues to this diagnosis (fig 66).). Clear cell change can be seen in mammary carcinoma, but is often patchy, and in carcinomas from other sites.
Conventional renal cell carcinoma is usually positive for the renal cell carcinoma marker (90%), whereas only about 15% of breast cancers are positive,77 and stromal cells could be positive.78 CD10 is present in a high proportion of conventional and papillary renal cell carcinomas (90%), commonly seen in other genitourinary and gastrointestinal tumours, but is uncommon in breast cancer (5%).79 Oestrogen receptor, GCDFP‐15 and cytokeratin 7 are rarely expressed in conventional renal cell carcinoma,35,36,80 although cytokeratin 7 is more common in other histological types.81
Carcinoid tumours of the small bowel and appendix metastasise to the breast surprisingly commonly.10,15,17 Primary endocrine carcinomas of the breast and carcinoid tumours of the lung and gastrointestinal tract can be morphologically similar. Ductal carcinoma in situ is a useful discriminant in breast biopsy specimens.
Immunohistochemical analysis can provide some clues to the primary site of carcinoid tumours. Expression of CDX2 and CK20 favours gastrointestinal origin and TTF‐1 favours pulmonary origin.55,74,82 There seem to be no data on these three markers in breast neuroendocrine tumours. Oestrogen and progesterone receptor and GCDFP‐15 are often expressed by mammary neuroendocrine carcinomas.83 Progesterone receptor is expressed in some pancreatic endocrine tumours, but not in gastrointestinal or pulmonary carcinoid tumour84; oestrogen receptor is not expressed in any of these extramammary tumours.
Both primary and metastatic sarcomas in the breast are rare. Sarcoma is more commonly seen as a component of metaplastic carcinoma or phyllodes tumour. The limited tissue in a core biopsy specimen makes accurate diagnosis difficult unless there is a history (fig 77).). Thorough sampling, looking for areas of conventional carcinoma or small cohesive foci, and cytokeratin immunohistochemistry using a panel of antibodies are useful in diagnosing metaplastic carcinoma.85 A search for leaf‐like areas of benign epithelium and CD34 immunohistochemical analysis are helpful in diagnosing phyllodes tumour.85
The distinction between primary and secondary lymphoma of the breast is based on clinical criteria.86,87 A wide range of mammary lymphomas have been described, but the most common type, primary or secondary, is diffuse large B cell lymphoma.86,87 This is usually readily recognised as malignant on histological examination. The major pitfall is not to consider the possibility of lymphoma and misdiagnose the tumour as carcinoma (fig 8A8A).). The clue is the cytology of the cells, which are most commonly centroblastic and less often immunoblastic. Immunohistochemical analysis for lymphoid markers establishes the diagnosis (fig 8C8C).
Other common types of secondary mammary lymphoma are follicular, marginal zone and small lymphocytic lymphoma/chronic lymphocytic leukaemia.88 In low‐grade lymphomas, the differential diagnosis is with inflammatory disorders. A diagnostic clue is the dense monotonous nature of the infiltrate (fig 8D,E8D,E).). For follicular lymphoma, the important differential diagnosis is reactive germinal centres. Lymphoepithelial lesions are not restricted to marginal zone lymphoma. Immunohistochemistry and PCR for immunoglobulin heavy‐chain clones or translocations are often helpful. T cell lymphomas are uncommon89; clear cytoplasm is a useful pointer (fig 8F8F).). If the diagnosis of lymphoma is not straightforward, a specialist opinion is recommended.
Leukaemia occasionally involves the breast. The morphology of the blasts or more differentiated cells may give a clue to the diagnosis, but a high index of suspicion may be needed to make the correct diagnosis if there is no clinical history.87
Myeloma rarely involves the breast.87 The plasmacytic morphology and pattern of infiltration around lobules (fig 99)) suggest the diagnosis. Showing light‐chain restriction is important in establishing the diagnosis (fig 99).). CD38 and CD138 are useful markers of plasma cell differentiation, but neither is specific.90,91,92
Although metastases to the breast are uncommon, accurate diagnosis is important to ensure appropriate management. The diagnosis may be straightforward if there is a clinical history of extramammary malignancy, particularly if sections are available for comparison. The pathologist has a key role in considering the possibility of metastasis if the morphology of the tumour is not typical of a primary mammary tumour. As Jane Austen said “A lucky guess is never merely luck. There is always some talent in it”.93
H&E - haematoxylin and eosin
GCDFP‐15 - gross cystic disease fluid protein‐15
TTF‐1 - thyroid transcription factor‐1
Competing interests: None declared.