Cellient Atlas – Breast FNA


Andrew H. Fischer, M.D

Note: The cell block images presented here were generated using a manual method during development of the automated instrument.

FNA of the breast is an effective means of identifying breast cancers to allow definitive treatment, while accurately excluding malignancy in most benign lesions. [1, 2] Compared to core biopsy, there is decreased morbidity, including hematoma, infection, pain, and risk of seeding of the biopsy track. Nevertheless, the past decade has seen a decline in breast FNA in favor of more aggressive core biopsy techniques. Some pathologists prefer the histologic evaluation of core biopsies because they can be analyzed relatively quickly and easily, and they allow immunohistochemistry (IHC) to be applied. Cell blocks of breast FNA’s offer these same advantages. Combining FNA with core biopsies has been shown to increase diagnostic accuracy. [3] Our recent experience suggests that combining a cytology preparation of a breast FNA with a cell block can also combine the advantages of both approaches. [4]

Current cytologic classification of breast cytology samples [5] includes 5 categories: Negative for malignant cells (which can encompass mild proliferative changes), Atypical, Suspicious, Malignant and Unsatisfactory for diagnosis. The atypical category is a major dilemma for breast FNA. Criteria for atypical lesions have shown poor reproducibility, and atypical breast FNA’s are found on follow-up to correspond to cancer in 1/3 to half of the cases. [2, 3, 6] Because of the high rate of cancer following an “atypical” breast FNA result, biopsy is generally recommended. [5] The suspicious category is also problematic. The surgeon’s decision to perform cancer surgery at the outset (mastectomy or lumpectomy with attempt to achieve adequate resection margins, together with lymph node sampling) is important to avoid multiple costly surgeries that can lead to sub-optimal cosmetic results. To avoid over treatment of benign lesions and achieve optimal cosmetic results, surgeons may need to perform a second diagnostic biopsy following a suspicious cytology FNA diagnosis.

The major problem in classifying proliferative ductal lesions by cytology is that tissue-level changes define the degree of hyperplasia rather than cytologic changes. [7] Hyperplasia is defined as the stratification of ductal cells away from the basement membrane microenvironment. The degree of hyperplasia is graded histologically into usual ductal hyperplasia and atypical ductal hyperplasia.

The major problem in classifying proliferative ductal lesions by cytology is that tissue-level changes define the degree of hyperplasia rather than cytologic changes. [7] Hyperplasia is defined as the stratification of ductal cells away from the basement membrane microenvironment. The degree of hyperplasia is graded histologically into usual ductal hyperplasia and atypical ductal hyperplasia.

In usual ductal hyperplasia, polarity between adjacent cells is often focally maintained with alignment of the long axis of cells in the same direction. This alignment gives a streaming, or vague “school of fish”, appearance to the stratified population. The long axis of the cells in usual hyperplasia also tends to align itself with any residual lumina within the duct, and the residual lumina tend to have an elongated shape with a fuzzy edge. Nuclear spacing in usual hyperplasia tends to vary over the diameter of the duct. Usual hyperplasia often shows an admixture of a distinctly different myoepithelial cell population admixed with the ductal cells. Note that pagetoid extension of mammary carcinoma in benign ducts can simulate an admixture of cell types. [7] Finally, in usual hyperplasia, the overall appearance of the cells may vary predictably depending on how far the cells have stratified away from the basement membrane. Commonly, the nucleus becomes darker and cytoplasm becomes denser as the cells stratify further from the native basement membrane zone.[8]

Atypical ductal hyperplasia is characterized by a stratifying population with loss of shared polarity (no streaming) between adjacent cells, no apparent admixed myoepithelial cells, residual lumina that become more smoothly rounded (“punched out”) with the long axis of the nuclei randomized with respect to the edges of the lumina, and no apparent maturation of the cells as they stratify further from the basement membrane zone. [8] In most cases, these features are easy to note at low magnification in histologic sections. Ductal carcinoma in situ is diagnosed when the above features of atypical hyperplasia are unequivocally developed and the population of cells extends over many ducts.

Many of these diagnostic histologic features that distinguish the degree of hyperplasia are difficult or impossible to discern in cytology preparations unless high magnification is used to focus up and down through piles of cells. On the other hand, there are some features that cytologists can use to characterize and recognize ductal proliferations that surgical pathologists cannot use. Discohesion of the ductal cells is one important feature. Cell blocks capture individual discohesive cells to allow this important feature to be noted.

It is important to note that nuclear atypia is not characteristic of low grade ductal carcinoma in situ or atypical hyperplasia. Nuclear atypia is a feature of high grade ductal carcinomas. Cell blocks preserve nuclear features crisply, comparable to cytology preparations, allowing both the low grade architectural changes and the high grade cytologic changes to be detected.

A difficult differential diagnosis in breast FNA is the distinction between fibroadenoma, papilloma and papillary carcinoma. The distinction is important because fibroadenomas, if confidently diagnosed, do not have to be excised. Central papillomas do not necessarily need to be excised, or require only gross excision. On the other hand, papillary carcinomas require careful complete excision with clear margins. The distinction between papilloma and papillary carcinoma is defined by the absence of a myoepithelial cell population in the latter, or the presence of stratification that meets architectural criteria for in-situ carcinoma. Myoepithelial cells can be difficult or impossible to discern in monolayer cytology preparations and papillomas can show considerable stratification and nuclear atypia. Thus the distinction of papillary carcinoma and papilloma is widely considered to be nearly impossible on cytology preparations alone. While some residual myoepithelial cells are often retained next to the basement membrane in ductal carcinoma in situ, a non-invasive papillary carcinoma infrequently shows residual myoepithelial cells. [7] Immunohistochemical staining for myoepithelial cells (calponin, p63, and smooth muscle actin) in cell block sections can be very useful to distinguish papillomas from papillary carcinomas. [9, 10, 11, 12]

Distinction of lobular from ductal carcinoma is difficult by cytopathology. The distinction can occasionally be important. Since lobular carcinoma in situ is sometimes not treated surgically, the rare occurrence of lobular carcinoma in situ as an incidental finding (e.g., colonizing a fibroadenoma) could lead to excessive surgery. On FNA cytology preparations, lobular carcinomas are generally very sparsely cellular and are easily under-diagnosed. Not only are there generally few cells, the cells can be very bland. Lack of polarity in the sparse cells, and the presence of “targetoid” mucin vacuoles is a helpful diagnostic trait of lobular carcinoma. Intracellular mucin is very rare in normal ductal cells, and its presence can be demonstrated in cell blocks. Lobular carcinoma is characterized by loss of E-Cadherin expression which can be detected in histologic sections by immunohistochemistry [12]. We have noted that the stromal tissue fragments obtained by FNA often have entrapped lobular carcinoma cells that can be seen in cell blocks, suggesting that the addition of a cell block to breast FNA can help improve the detection and specific diagnosis of lobular carcinoma.

Cytology preparations do not allow the presence of invasion to be diagnosed. [13] Since in situ cancers may not need lymph node sampling, this has been an important limitation of breast FNA for planning treatment. Through the use of cell blocks, we recently found that invasion can be diagnosed in a significant proportion of breast cancer FNA’s. [4]

In this chapter, we will show that combining cytology preparations with cell blocks allows the best of both worlds: micro-sized biopsies obtained by FNA allow cytologic as well as histologic criteria to be applied.


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