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The management of atypical intraductal lesions of the breast remains controversial. In the present study, the subsequent surgical excision results and follow-up data on 86 (3.65%) atypical intraductal lesions and 78 (3.31%) low-grade ductal carcinoma in situ (DCIS) from a cohort of 2358 needle biopsies were examined. There were 17 cases (0.72%) of pure flat epithelial atypia (FEA), 44 (1.87%) pure atypical ductal hyperplasia (ADH), three (0.13%) pure atypical lobular hyperplasia (ALH), 18 (0.76%) combined ADH + FEA, three (0.13%) combined ALH + FEA and one (0.04%) combined ALH + FEA + ADH. Subsequent surgical excisions were done in 53 cases and revealed the following incidences of malignancy: pure FEA (1/8); pure ADH (17/31); FEA + ADH (7/10); FEA + ALH (2/3); and FEA + ALH + ADH (0/1), with pure FEA showing significantly lower incidence of malignancy. In this cohort, there were 703 carcinomas including 155 DCIS with 78 cases (50.3%) being low-grade. FEA with ADH (and/or ALH) was present in 22 (28.2%) of these 78 cases of low-grade DCISs at surgical excisions. Pure FEA was not detected in any of the subsequently excised surgical materials of the atypical intraductal lesions nor the low-grade DCISs. Thus, pure FEA was very unusual in surgical specimens. When pure FEA is detected at needle biopsy, a wait and see approach can be adopted. However, when the FEA is associated with other concomitant atypical intraductal lesions, especially ADH, further excision should be contemplated. (Cancer Sci, doi: 10.1111/j.1349-7006.2012.02314.x, 2012)
The use of needle biopsy in evaluating calcifications detected at mammography (MMG) and/or suspicious malignant lesions detected at ultrasound has increased because of a rise in the frequency of screening. Many of these lesions represent atypical intraductal lesions such as flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH). These are morphologically similar to early type, low grade ductal carcinoma in situ (DCIS) or lobular carcinoma in situ. For FEA, there had been previous variations in its terminology, but since the World Health Organization (WHO) working group on breast tumors, introduced the term FEA, this was essentially adopted by many authors.[2-11]
To date the terminology is still confusing and far from uniform, sometimes FEA or ADH are used in lesions that are essentially or exclusively DCIS or are of uncertain malignant potential (indeterminate, B3), resulting in variations in the treatment of patients with these lesions. Although several previous reports indicated the biological and clinical significance and close genetic relationship of FEA and ADH, the management of these lesions remains controversial,[4-10] and this is now a topical issue in Japan. In addition, there is limited experience of these atypical intraductal lesions reported from Asia. Thus, a detailed evaluation was undertaken from a large Asian cohort.
In the present study, needle biopsy diagnosed atypical intraductal lesions (i.e. FEA, ALH and ADH), and low-grade DCIS, which showed similar morphology (non-comedo type, such as the Van-Nuys classification, were investigated from two perspectives: (i) the frequency and distribution of FEA, either pure or associated with other atypical intraductal and/or low-grade DCIS that were detected at needle biopsies (core and Mammotome), and their associated and subsequent risks for malignancy based on surgical resection specimens and/or clinical follow-up data; and (ii) the frequency and distribution of subtypes of low-grade DCIS in biopsies (core and Mammotome); and on the presence of FEA, whether in pure form or in association with other atypical intraductal lesions (ADH,ALH), in the breast tissue adjacent to these low grade DCIS excision samples.
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In FEA, the strict terminology of “flat“ refers to lesions without bridging, micropapillary or a foothill-like appearance. These lesions are relatively rare compared to other atypical intraductal lesions in needle biopsy specimens and are also extremely rare in the subsequent surgical specimens. The frequency of pure FEA detected in the present study was low (0.72%), even when compared to others that reported an incidence of about 3.7%.[5, 13] One of the possible reasons for this discrepancy was the relatively recent starting in Japan (J-start) of ultrasound guided needle biopsies in 2008, and many benign lesions were biopsied. The other reason could be ethnic differences. The percentage of cases with FEA diagnosed at needle biopsy, that were upgraded to carcinoma at surgical excision specimens (12.5%) was similar to other studies, where it ranged from 0% to 21%.[4-6, 9-11, 16-18] In this study, it was shown that FEA, when present in combination with other atypical intraductal lesions (ADH, ALH), had a greater tendency to be upgraded on excisional surgical specimens. Similar findings have been reported in previous studies[5, 6, 11, 17] (Table 4). Although five cases of ADH and ADH + FEA were upgraded to carcinoma at excision within 3 months, these likely represented missed detection of carcinomas at needle biopsy rather than genuine disease evolution. Rather, most pure FEA did not develop or rapidly change into carcinoma, at least over a follow-up period of at least 1 year.
Table 4. Summary of published data demonstrating percentage cases atypical intraductal lesions at the biopsy specimens to final diagnosis on surgical excision
|Needle biopsy||FEA||FEA||FEA + ADH||ADH|
|Kunju and Kleer||0% (0/14)||21% (3/14)||11% (4/38)||38% (3/8)|
|Martel et al.||0% (0/5)||0% (0/5)||–||–|
|Chivukula et al.||0% (0/35)||14% (5/35)||16% (31/189)||11% (5/45)|
|Senetta et al.|| (?/36)||0% (0/36)||–||–|
|Piubello et al.||50% (10/20)||0% (0/20)||30% (3/10)||–|
|de Mascarel et al.|| (?/24)||0% (0/24)||– ||64% (32/50)|
| ||0% (0/7)||14% (1/7)||29% (2/7)||40% (6/15)|
| || (?/37) ||19% (7/37) ||29% (5/17)||53% (17/32)|
|Lavoué V et al.||23% (14/60)||13% (8/60)||–||–|
|Our study (2012)||0% (0/8)||13% (1/8)||70% (7/10)||55% (17/44)|
In the literature, most reports on atypical intraductal lesions focused on their progression to carcinomas.[4-11, 16] Although a few reports described high percentage of pure FEA in the subsequent surgical materials,[5, 10] the current findings, like many others[4, 6, 9, 16, 17] demonstrated that pure FEA was rarely seen in surgical specimens excised for atypical epithelial proliferation and DCIS (Table 4). Thus, it is important to strictly distinguish between pure FEA and FEA mixed with ADH (or ALH) in needle biopsies or between FEA and columnar cell change and columnar cell hyperplasia. FEA is defined as “a presumably neoplastic intraductal alteration characterized by replacement of the native epithelial cells by a single or three to five layers of mildly atypical cells.” This definition, as detailed in the WHO classification and other previous reports,[2, 13] implies that FEA should be considered a precursor to or an early stage lesion in the development of certain forms of DCIS. At the histologic diagnostic level, morphological diagnosis may sometimes be difficult, and unlike ADH, immunohistochemistry has not been found to be useful.
In the current study, all biopsies except one case with stand alone pure FEA (without other atypical intraductal lesions) did not progress to malignancy. Furthermore, among the low-grade DCIS group, there was a 28% incidence of FEA in combination with other low-grade DCIS subtypes or atypical intraductal lesions, compared to a reported 34%. For all the malignant cases that were excised, FEA was always associated with ADH, ALH and other DCIS subtypes, and there was no case of pure FEA coexisting with low grade DCIS. These observations may be construed as evidence that pure FEA devoid of other atypical intraductal lesions has very low risk of being associated with or progressing to malignancy. These observations were also reported by others.[5, 6, 9, 16, 17] Thus, surgical excision may not be necessary when pure FEA is encountered in needle biopsies because its characteristics did not change over a follow-up period of at least 1 year. However when FEA, together with ADH and/or other atypical lesions were detected in needle biopsy specimens, further resection would be deemed necessary and these cases should be closed monitored.
In agreement with the current findings, others reported that FEA was not associated with cancer at re-excision, when detected alone using strict criteria at biopsy. Furthermore, many of the current samples were Mammotome (11 G) specimens, which represented extensive sampling (similar to other studies)[5, 9] thus, these studies were potentially more likely to have sampled the lesions, compared to those using core needles biopsy (14 G) specimens.[4, 6, 7, 10, 16] Moreover, even if pure FEA were present, these lesions were tiny and not extensive, because pure FEA has not been found in the surgical specimens of low grade DCIS. Furthermore, follow-up data in the current series showed that these low grade DCIS and the atypical intraductal lesions did not recur or metastasize over a follow-up period of at least 1 year. Thus, in dealing with this biologically indolent group of lesions, particularly pure FEA in a core biopsy, excision is not mandatory.[5, 9, 16] It should also be noted that a firm diagnosis of pure FEA on needle biopsy can only be made with adequate tissue at sampling, as theoretically an inadequate sample may miss foci of other atypical intraductal lesions. This is less of a problem for Mammotome as more tissue is extracted. Most of the cases in this cohort were taken by Mammotome.
In conclusion, pure FEA rarely occurred in needle biopsy specimens, and was unusual in surgical excision specimens. Although the follow-up period is short in the present study and further investigation is needed, pure FEA did not exhibit significant change over time, pathologically and radiologically over at least 1 year. Thus, pure FEA when encountered in needle biopsy does not warrant immediate mandatory further surgical excision. A wait-and-see approach with follow up may be a suitable alternative. However, cases with both FEA and ADH showed a high percentage of association with malignancies, and these cases should be further excised and closely monitored. In this context, adherence to strict diagnostic criteria for pure FEA and ADH is of utmost importance, especially in the setting of needle biopsy.