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Fine Needle Aspiration Cytology

BREAST
Grace T. McKee, MD

Introduction

The breast is composed of fat and stroma that support glandular tissue, a branching ductal system that leads to 6-10 main ducts, which open onto the nipple. Both benign and malignant lesions develop in the breast. In young women fibroadenomas are common lesions but as women get older, fibrocystic changes tend to be more common. Other benign lesions include fat necrosis and inflammatory conditions such as breast abscess and mastitis. Less common benign lesions such as hamartomas and pseudoangiomatous hyperplasia can occur. Ductal hyperplasia forms part of fibrocystic changes. Atypical ductal hyperplasia can be difficult to distinguish from low grade ductal carcinoma in situ and these lesions represent a spectrum of disease that can develop into breast carcinoma. Radiation changes can produce a mass, which may appear atypical on aspiration cytology. Similarly, pregnancy and lactational changes can also be mistaken for malignancy on aspirates hence clinical information is essential for an accurate cytological diagnosis.

Malignancies in the breast may be primary or metastatic Those metastatic to the breast include lymphoma, malignant melanoma and other secondary tumors such as renal, bronchial, ovarian or pulmonary carcinomas. Most significant from a diagnostic perspective is primary breast carcinoma is the ductal type, not otherwise specified (NOS). The second most common primary mammary neoplasm is lobular carcinoma. Ductal carcinoma in situ and lobular carcinoma in situ are easily diagnosed on excision biopsies but are more difficult to diagnose with confidence on cytology.

Breast cytology has a role for both screening and diagnostic purposes. Any lesion detected on mammographic screening can be sampled with a fine needle, by direct aspiration if palpable or by stereotactic or ultrasound guidance if non-palpable. If the cytology sample is unsatisfactory or equivocal, core biopsy or frozen section can be utilized. Palpable breast masses are easily aspirated and can be quickly processed for a rapid diagnosis.

Fine-needle aspiration cytology is a useful tool in the diagnosis of breast lesions, both palpable and non-palpable. It is a safe, quick, inexpensive (as compared to core biopsies), and relatively painless procedure, and can be performed by clinicians as well as pathologists. In the hands of cytopathologists the inadequacy rate is low as rapid stains can be performed to evaluate specimen adequacy and the procedure repeated if necessary. Cyto-histological correlation is excellent in the hands of experienced cytopathologists. One minor disadvantage of fine-needle aspirates is that it is not always possible to distinguish between invasive and in situ lesions, but core biopsies too have similar problems in some cases.

The material aspirated is either smeared on a glass slide or expelled into Cytolyt® solution, and the needle is rinsed with the same solution for each pass made. The fluid can be used to make several almost identical slides thus enabling the lab to save material for special stains such as estrogen and progesterone receptors and HER2/neu protein over-expression.

CYTOLOGICAL FEATURES
Benign
Normal breast
yields only fat, stroma and a few benign ductal cells. Benign normal breast is rarely aspirated unless the actual lesion is missed by the needle. In fact, aspirates from normal breast would not comply with the widely observed criterion for an adequate breast aspirate: at least five to six clusters of epithelial cells. Exceptions to this rule include fat necrosis and inflammatory lesions.

Mastitis and breast abscess aspirates contain abundant neutrophils, histiocytes, multinucleated giant histiocytes, a few degenerating epithelial cells and proteinaceous material that can mimic necrosis. They are not uncommon findings in lactating women. Fat necrosis develops after trauma, either because of a direct blow to the breast or following surgery or radiation therapy. Clinically and mammographically fat necrosis mimics breast carcinoma, with a hard, irregular mass. However, the aspirate is diagnostic, as it is composed of degenerating adipocytes with abundant lipophages.

Fibroadenoma presents as a firm, smooth, mobile breast mass. It usually feels rubbery and grips the needle tip. Aspirates are usually cellular with large branching sheets of benign ductal cells, with a sprinkling of 'sesame seeds' on the surface – myoepithelial cells. In ThinPrep smears the single background myoepithelial cells tend to accumulate adjacent to the ductal cells. The ductal cells often show overlapping, suggesting an element of ductal hyperplasia. Stromal fragments of varying sizes are seen, containing spindled nuclei.

Low grade phyllodes tumors are also fibroepithelial in composition, with the glandular element closely mimicking that of fibroadenoma. However, ductal hyperplasia is much more common in phyllodes tumors. The stromal component tends to be prominent, with large stromal fragments that are hypercellular. Abundant stromal cell groups may also be noted. Malignant phyllodes tumors show unequivocal features of malignancy.

Fibrocystic change is a fairly common lesion encompassing cystic change with apocrine metaplasia, ductal hyperplasia of usual type, and other forms of epitheliosis. Cytological appearances include sheets and groups of overlapping benign ductal cells with myoepithelial cells, apocrine metaplasia, foamy macrophages and calcium. The features can mimic those of fibroadenoma cytologically, but the typical clinical finding is an ill-defined thickening or ridge rather than the smooth mobile mass of fibroadenoma. Cystic changes can progress to form palpable cysts which are easily aspirated. The fluid may be clear and colorless or turbid, brown, green or bloodstained. Cyst fluids contain proteinaceous material, benign ductal cells that may appear degenerated or mildly atypical, apocrine metaplastic cells, and foamy macrophages. Brown or green cyst fluid usually indicates prior bleeding and this is confirmed by the presence of hemosiderin-laden macrophages on the slide. Apocrine metaplastic cells have abundant granular cytoplasm, round nuclei and prominent nucleoli. They can be binucleate and may appear atypical as the nuclear size is variable.

Collagenous spherulosis is a benign lesion that may accompany ductal or lobular hyperplasia. Aspirates show globules of extracellular material (which stain pale blue with the Papanicolaou stain and magenta with DiffQuik), benign ductal, apocrine metaplasia and myoepithelial cells. The differential diagnosis includes adenoid cystic carcinoma.

Malignant
Features that are suggestive of malignancy include loss of cell cohesion, increase in cell and/or nuclear size, irregularity of the nuclear membrane, clumping and uneven distribution of chromatin, as well multiple, abnormal nucleoli. Single nucleoli may be seen in reactive conditions and are not a criterion of malignancy on their own. Myoepithelial cells, which are abundant in benign proliferative lesions, are not seen in aspirates of invasive breast carcinoma.

Ductal carcinoma tends to be unilateral. It presents as a firm to hard, irregular mass clinically, with a characteristic mammographic appearance of a mass, a spiculated lesion or microcalcifications. Although ductal carcinoma in situ is thought to precede invasive ductal carcinoma, it may also accompany invasive lobular carcinoma. Similarly, lobular carcinoma in situ may be associated with ductal carcinoma as well as invasive lobular carcinoma. Ductal carcinoma in situ aspirates show malignant features but may also display myoepithelial cells overlying the cell clusters. Invasive ductal carcinoma (NOS) yields cellular aspirates composed of large, often pleomorphic tumor cells. Low grade ductal carcinomas can be difficult to distinguish from benign ductal cells. Invasion is suggested by the presence of tumor cells infiltrating between adipocytes.

Lobular carcinoma is often bilateral. Clinically the tumor is ill-defined and has no typical mammographic appearance. Lobular carcinoma in situ is seen as rounded clusters of small malignant cells, some with intracytoplasmic vacuoles, often with overlying myoepithelial cells. Invasive lobular carcinoma aspirates are scant, often resulting in an 'unsatisfactory' or 'atypical' report. The cells are smaller than in ductal carcinoma, often single with eccentric nuclei and intracytoplasmic vacuoles. Nucleoli are not usually seen. The cells often lie in a single file. Signet ring cells may be seen in lobular carcinoma aspirates.

There are also special types of ductal carcinoma that occur such as tubular, colloid (mucinous), metaplastic, medullary, apocrine and squamous. The definition of many of these special types of breast tumors is based on evidence that more than 90% of the lesion shows the typical characteristics of that type. As cytology samples only part of the tumor it is not accurate to categorize these tumors as tubular or mucinous cytologically. The suspicion can be raised in the report by including a description such as "ductal carcinoma with mucinous or tubular features" rather than a definite type, which might possibly differ from that of the excision specimen. Tubular carcinomas are composed of tubular and acinar structures. Mucinous carcinoma aspirates are often grossly mucoid and show abundant mucin on the smear. Certain rarities such as adenoid cystic carcinoma, identical to that seen in the salivary gland, may also develop. This tumor mimics benign collagenous spherulosis in that it also contains extracellular hyaline material with the same staining characteristics, but in the form of both globules and tubular or cylindrical structures. The accompanying tumor cells are small and bland with little cytoplasm, but benign ductal, apocrine and metaplastic cells are not seen.

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