Some lesions may present particular diagnostic problems in core samples.
A potential pitfall includes focal lactational change, which may be seen in women who are neither lactating, nor pregnant, and indeed are nulliparous and/or postmenopausal. The involved acini are usually lured by plump vacuolated cells with a “hobnail” architecture but, less frequently, may appear atypical with irregular, large, or pyknotic nuclei. The epithelial cells may appear degenerative, and rarely the benign nature of the process may be mistaken for cancerisation of lobules by DCIS. The recognition of the vacuolation of the cytoplasm and the typical hobnail architecture will enable the correct diagnosis to be established.
Mild atypia of the epithelium within lobular units is one of the most common problems encountered in core biopsy samples. Care must be taken not to over diagnose such minimal degrees of atypia, which may represent usual epithelial hyperplasia, apocrine change, or reactive changes (for example, adjacent to a previous sampling procedure). Usual epithelial hyperplasia and other forms of benign hyperplasia, such as that of the gynaecomastoid type, are commonly seen in cores from benign fibroadenomas. This often shows apparent discohesion as a result of the trauma of the core biopsy sampling process, and “telescoping” of the epithelium is seen within the duct spaces, thus resembling a more sinister epithelial proliferative process. As with usual epithelial hyperplasia in surgical excision specimens, the lack of uniformity and distribution/streaming of the epithelial cells with bland nuclear features and paucity of mitoses is of assistance in reaching a diagnosis. Usual epithelial hyperplasia of the gynaecomastoid type with a micropapillary architecture should not be mistaken for micropapillary ADH/DCIS.
There is a risk of over diagnosis of invasive carcinoma when confronted by sclerosing adenosis in a core biopsy, because the normal lobular arrangement may be less apparent than on an excision biopsy specimen. Immunohistochemical staining for collagen IV, laminin, and/or smooth muscle actin to demonstrate the presence of a basement membrane and a dual epithelial/myoepithelial layer, respectively, can be extremely useful in this situation. The stromal lack of fibroplasia, generally seen in an invasive carcinoma, may be helpful in achieving a correct diagnosis. In difficult cases, immunohistochemistry for smooth muscle actin may be invaluable; the presence of the myoepithelial component present in sclerosing lesions and absent in tubular carcinomas can be confirmatory.
Radiotherapy induced changes to the breast may be difficult to differentiate from foci of recurrent or residual carcinoma, both in situ and invasive. Radiation induces a degree of atypia of the breast epithelium and also in the histiocyte population, which is often prominent after radiotherapy and recent surgery. The macrophages may also show degenerative features, so that carcinoma cells may conversely mimic macrophages. Immunocytochemistry can be helpful in difficult cases because irradiated neoplastic cells retain cytokeratin expression, whereas macrophages show a histiocytic phenotype—for example, CD68 expression.
Apocrine atypia, particularly in association with a sclerosing lesion such as sclerosing adenosis (so called “apocrine adenosis”), may be especially difficult to identify correctly in non-operative diagnostic samples. In core biopsy large nuclei, often with prominent nucleoli, may be mistaken for DCIS if pleomorphism is also present. The typical granular eosinophilic cytoplasmic appearance of apocrine cells should be sought. Pure apocrine DCIS is relatively rare and when an apocrine proliferation is seen within ducts in a core biopsy, additional features of malignancy such as significant atypia, intraluminal necrosis, the presence of mitoses, and multiple duct involvement should be sought for confirmatory evidence. Mild or moderate degrees of apocrine proliferation with atypical features in a duct space should be assessed with caution, and it may be prudent not to record a definite diagnosis, but to classify such a process as B3, of uncertain malignant potential. Conversely, papillary apocrine change should not be mistakenly classified as other than benign B2.
Stromal proliferations may cause considerable difficulties in diagnosis in core biopsy samples. Occasionally, a second biopsy sample will be taken from a patient containing a fibroblastic proliferation which may represent the target lesion, but which may reflect tissue reaction and repair at the previous biopsy site. If the lesion represents the core site, an associated histiocyte reaction or indeed fat necrosis may be present, and haemosiderin laden macrophages can be seen. Sometimes fibroblastic stroma may be identified in a sample from a patient who has not undergone previous FNAC or core biopsy, and which may represent a spindle cell proliferation such as fibromatosis or part of a spindle cell tumour, such as a nerve sheath tumour or myofibroblastoma. Immunohistochemistry may prove unhelpful and a multidisciplinary approach must be applied to the clinical, radiological, and histopathological features. When a definitive histological diagnosis cannot be made the abnormality should be reported as a spindle cell lesion of uncertain histogenesis or nature and classified as B3.
Small foci of invasive lobular carcinoma can be missed in histological sections and be dismissed as chronic inflammation or stromal cells. The targetoid infiltrative pattern of classic lobular carcinoma may be of assistance, but a reactive lymphocyte process can also have a periductal or perilobular distribution. Cytokeratin immunohistochemistry, to demonstrate the neoplastic cells, is of value in difficult cases, but recognition of the abnormal cell proliferation requires vigilance because the features can be subtle.
“Small foci of invasive lobular carcinoma can be missed in histological sections and be dismissed as chronic inflammation or stromal cells”
Malignant lymphoma may rarely be identified in core biopsies and should be classified as B5 malignant. Most of these lesions are of high grade B cell morphology and may mimic epithelial malignancy. Low grade lymphomas may be more difficult to distinguish, mimicking a chronic inflammatory processes. To avoid misclassification, a panel of lymphoid markers may be necessary to demonstrate the immunophenotype of the cells present and to allow correct diagnosis.
Metastasis to the breast from malignancies derived elsewhere is well recognised, although rarely biopsied. A full clinical history is essential to avoid the misdiagnosis of a metastatic carcinoma as a primary breast carcinoma. A panel of antibodies frequently allows identification of the likely site of a metastatic adenocarcinoma and enables appropriate clinical investigation/management. Breast carcinomas usually express cytokeratin 7 and 18 (and not cytokeratin 20), epithelial membrane antigen, and carcinoembryonic antigen/non-specific crossreacting antigen; in addition, approximately 80% will express ER.
Metaplastic carcinomas, or very rarely primary sarcomas, may mimic stromal proliferations, and a high index of suspicion may enable confirmatory diagnosis by immunohistochemical examination with a range of anticytokeratin antibodies (at least one broad spectrum and a high molecular weight cytokeratin, such as MNF116 and LP34). Primary breast sarcomas are rare. They most frequently originate in association with phyllodes tumours, but in core biopsy specimens an epithelial component is often not present. The most common phyllodes associated sarcomas seen are liposarcomas and fibrosarcomas, although osteosarcomas, chondrosarcomas, and rhabdomyosarcomas can be identified. Angiosarcomas may be a cause of a false negative diagnosis because they may be relatively subtle and bland and may be mistaken for radiotherapy induced changes, particularly when they occur in this situation in the treated breast. Primary leiomyosarcoma (and leiomyoma) may be found in the breast; leiomyomas are most often seen in a retroareolar site. All these lesions can be difficult or impossible to diagnose definitively in core samples. A high index of suspicion and the judicious use of immunohistochemistry can facilitate or support a diagnosis, but non-diagnostic classification as B3 or B4 is often prudent.