Flat Epithelial Atypia (Atypical Lobular Hyperplasia) Dr. Laura C. Collins

Case History A 44 year old woman was found to have microcalcifications on a screening mammogram. An excisional biopsy was performed following wire localisation. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Microscopic description This lesion is characterised by Terminal Duct Lobular Units (TDLUs) which display variably dilated acini lined by one to several layers of epithelial cells that are cuboidal to columnar in shape. The cells show low-grade cytologic atypia characterised by the presence of relatively monomorphic round to ovoid nuclei with evenly dispersed nuclear chromatin resembling the cells comprising low grade ductal carcinoma in situ. The nuclei are not regularly oriented perpendicular to the basement membrane. There is a slight increase in the nuclear/cytoplasmic ratio. It is because of this increased nuclear/cytoplasmic ratio, that the involved TDLUs often have a more basophilic appearance than normal TDLUs at scanning magnification. Cellular and nuclear stratification can be appreciated. Nucleoli may be prominent. Mitotic figures may be seen but are uncommon. In some cases, apical cytoplasmic snouts or blebs may be prominent or exaggerated, and the cells cytologically may resemble those comprising the cells of tubular carcinoma. The epithelial cells in Flat Epithelial Atypia (FEA) lesions may form small mounds, tufts or micropapillations. However, complex architectural patterns, such as well-developed, bulbous micropapillations, rigid cellular bridges, bars and arcades, or sieve-like fenestrations, with evidence of cellular polarization are absent. Thus, 'flat' is a relative term, denoting the absence of the complex architectural patterns described above. These lesions also frequently show intraluminal calcifications which in some instances may be in the form of psammoma bodies. A variable lymphocytic infiltrate may be present in the stroma surrounding spaces involved by FEA. Adjacent to the dilated TDLUs in our case, are lobules that are somewhat expanded by a population of cells, cytologically characteristic of lobular carcinoma in situ. Diagnosis: Flat epithelial atypia (Atypical lobular hyperplasia) The World Health Organisation Working Group on the Pathology and Genetics of Tumours of the Breast definition of flat epithelial atypia is of a lesion of the terminal duct lobular units (TDLUs) in which the native epithelial cells are replaced by one to several layers of epithelial cells that show low grade cytologic atypia [1] . Differential Diagnoses There are a number of different entities that enter the differential diagnosis for flat epithelial atypia. Firstly, the lesion needs to be distinguished from microcysts, which on low power examination flat epithelial atypia resembles. High power examination of dilated TDLUs is required to appreciate the subtle cytologic atypia present in flat epithelial atypia [2] but absent in microcysts, which are characterized by an attenuated cuboidal epithelium. Apocrine metaplasia can also enter the differential diagnosis of flat epithelial atypia. The nuclei of apocrine metaplasia are rounded like those seen in flat epithelial atypia and have prominent nucleoli. However, apocrine metaplastic cells have abundant, granular, pink cytoplasm whereas the cells of flat epithelial atypia exhibit a higher nuclear to cytoplasmic ratio and generally possess a more basophilic appearing cytoplasm. Moreover, apocrine metaplastic epithelium lacks the ER expression and bcl2 overexpression characteristic of FEA [3] . Columnar cells lesions (without atypia) tend to have ovoid nuclei without prominent nucleoli whereas in flat epithelial atypia the nuclei tend to be rounded with or without nucleoli as mentioned above. The features useful in making the distinction between columnar cell change, columnar cell hyperplasia and FEA are provided in Table 1. It is more important to distinguish both columnar cell change and columnar cell hyperplasia from FEA than it is to distinguish columnar cell change and columnar cell hyperplasia from each other. The ability of pathologists to reproducibly distinguish non-atypical columnar cell lesions (ie, columnar cell change and columnar cell hyperplasia) from FEA has been addressed in several recent studies. Reproducibility ranges from fair to excellent in these studies; with excellent interobserver agreement being reported with the use of standardized diagnostic criteria. [4, 5, 6] Table 1 Histologic features of columnar cell change, columnar cell hyperplasia, and flat epithelial atypia. Columnar Cell Change Columnar Cell Hyperplasia Flat Epithelial Atypia Topography Enlarged TDLUs with variably dilated acini; acini tend to be irregular in contour Enlarged TDLUs with variably dilated acini; acini tend to be irregular in countour Enlarged TDLUs with variably dilated acini; acini tend to be well rounded; involved TDLUs often more basophilic than normal TDLUs Architecture One to two layers of columnar cells Cellular stratification, with more than two cell layers of columnar cells, sometimes forming tufts or mounds; complex architectural patterns not present One to several layers of cuboidal to columnar epithelial cells; complex architectural patterns not present Cytology Columnar cells with uniform ovoid to elongated nuclei; nucleoli absent or inconspicuous Columnar cells with uniform ovoid to elongated nuclei; nucleoli absent or inconspicuous; hobnail cells may be present Cuboidal to columnar cells with cytologic atypia, usually low-grade (may be subtle); cells may resemble those of tubular carcinoma Apical snouts Often present; usually not prominent Often present; may be exaggerated Often present; may be exaggerated Intraluminal secretions May be present; usually not prominent May be present and prominent May be present and prominent Calcifications May be present Often present; may be psammomatous Often present; may be psammomatous When flat epithelial atypia becomes more proliferative and begins to show architectural atypia in the form or bridges and arcades, the differential diagnostic considerations include atypical ductal hyperplasia and ductal carcinoma in situ. Lesions with low grade cytologic atypia and sufficient architectural atypia to be classified as either Atypical Ductal Hyperplasia (ADH) or Ductal Carcinoma in situ (DCIS) should be diagnosed as such. [7, 8, 9, 10] Lesions which architecturally fall short of the histologic criteria for ADH or DCIS should be classified as FEA. Flat lesions without architectural atypia but in which there is high grade cytologic atypia should be categorised as high grade DCIS and not FEA. [11] Immunophenotype The majority of the cells in FEA express cytokeratin 19 [12] and lack expression of HMW cytokeratins. [13, 14] Therefore, the absence of HMW-CK expression cannot be used to distinguish FEA from columnar cell lesions without atypia, as has been done for atypical intraductal proliferations (such as ADH and DCIS which lack or show markedly reduced HMW-CK expression) from usual ductal hyperplasias (which typically show a mosaic pattern of HMW-CK expression). [13, 14, 15] Columnar cell lesions and FEA typically exhibit intense nuclear expression of estrogen receptor [3, 16, 17, 18, 19, 20, 21] and progesterone receptor in the majority of the cells. [20, 21] Overall, the cells comprising FEA appear to have a higher proliferation rate and less apoptosis than normal TDLUs, when looking at proportion of cells stained with cyclin D1 or Ki-67 and the anti-apoptic protein bcl-2. [20] Genetic Alterations Recent studies have begun to investigate the genetic alterations in FEA. Moinfar et al showed loss of heterozygosity (LOH) at one or more of the eight loci evaluated in nine of 13 cases of 'DIN-flat monomorphic type' (FEA) and further, that the genetic alterations in these lesions were the same as those in the associated DCIS or invasive cancer. [2] In that study, the most common losses were at 3p and 11q. In another study using comparative genomic hybridization to evaluate 81 lesions from 18 patients, Simpson et al found genomic changes not only in examples of FEA but also in examples of columnar cell change and columnar cell hyperplasia . [21] In addition, in five of eight cases, there were overlaps in the molecular profiles of the columnar cell lesions/FEA and co-existent DCIS and invasive cancer, implying an evolutionary relationship. In another study, Dabbs et al examined the spectrum of columnar cell lesions for LOH at 10 loci. [22] Losses were seen in 10 of 15 examples of atypical columnar cell hyperplasia/FEA. In this study, losses were most prevalent at 9q, 10q, 17p and 17q. Again, some of the observed genetic alterations in the columnar cell lesions were similar to those seen in the associated DCIS and invasive carcinoma suggesting a precursor-product relationship. Clinical significance Given the wide variety of terms that have been applied to FEA, it is difficult to determine the clinical significance of this finding. Nevertheless, several observational studies have clearly demonstrated that FEA may co-exist with areas of well-developed ADH, LG-DCIS and even tubular carcinoma and that the cells comprising the FEA share morphologic and immunophenotypic features with the cells comprising the above mentioned lesions. There is also a well documented association between FEA and lobular neoplasia (ALH or LCIS). [23, 24, 25] There have only been three follow-up studies that have attempted to address the clinical significance of FEA. Eusebi et al retrospectively identified 25 patients with so-called 'clinging carcinoma' of the flat monomorphic type (lesions that would now be considered FEA) in a review of 9000 breast biopsies originally considered to be benign. [26] Only one of these patients developed a 'local recurrence' after an average follow-up of 19.2 years. It should be noted, however, that the 'local recurrence' in this patient was histologically identical to the original 'clinging carcinoma' and as such it is not possible to determine if this represents residual disease due to inadequate excision or a true local recurrence. No patient developed invasive carcinoma. In a randomised clinical trial comparing excision and radiation therapy to excision alone for women with DCIS for the European Organisation for Research and Treatment of Cancer (EORTC) 10853 study, 59 patients with clinging carcinoma of the low nuclear grade type were identified . [27] There have been no local recurrences among these 59 patients with a median follow-up of 5.4 years. Most recently, de Mascarel et al reported on the outcome of 115 patients with FEA who had been treated with excision alone (n=70) or excision and radiation therapy (n=45). [28] Three patients have developed recurrent FEA in the ipsilateral breast and three patients have developed ipsilateral invasive breast cancer at one, seven and 12 years following the original diagnosis (two in the excision alone arm and one in the excision and radiation therapy arm); with a median follow-up of 13.3 years. The results of these follow-up studies suggest that when present as an isolated lesion, the risk of progression of FEA to invasive carcinoma is extremely low. Management The limited data available suggest that FEA encountered on a core needle biopsy requires excision, as a worse lesion is present in up to one third of cases. [29, 30, 31, 32] When present in an excisional biopsy, the presence of FEA should precipitate careful search for areas of diagnostic ADH or even low grade DCIS. FEA may also be seen in association with lobular neoplasia (as in our case) or tubular carcinoma. Additional levels should be obtained and all remaining breast parenchyma should be submitted for evaluation. More problematic is the issue of whether to include in measurement of extent of DCIS, areas of adjacent FEA; similarly the presence of FEA at the margin of a specimen in which areas of diagnostic DCIS are present is problematic. Given the currently available data that indicate a very low risk of progression to invasive cancer, it is our practice not to take into consideration adjacent FEA in the measurement of an area of co-existent DCIS or in the evaluation of margin status. Conclusion Flat epithelial atypia is being encountered with increasing frequency due to the widespread use of screening mammography. Recent studies have begun to provide insights into the biological and clinical significance of these lesions. However, additional morphologic, immunophenotypic and genetic studies are needed to better define the relationships between these flat atypical lesions to DCIS and to invasive breast cancer. Emerging data suggest that these flat epithelial atypias may be neoplastic lesions that represent the earliest form of low grade DCIS. Despite this, the limited available clinical follow-up data suggest that the risk of local recurrence or progression of these lesions to invasive cancer is quite low, supporting the notion that categorizing such lesions as 'clinging carcinoma' and managing them as if they were fully developed DCIS will result in overtreatment of many patients. Thus, at this time, the appropriate management of patients whose breast biopsies show flat epithelial atypia in the absence of diagnostic areas of ADH or DCIS is unknown and requires evaluation in further clinical outcome studies. 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