Pathology and Molecular Biology of Pre-invasive Breast Lesions
Moderator: Werner Boecker
Section 1 -
Columnar Cell Lesions and Flat Epithelial Atypia of the Breast
Stuart J. Schnitt and Laura C. Collins
Beth Israel Deaconess Medical Center and Harvard Medical School , Boston , MA
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Lesions characterized by the presence of columnar epithelial cells lining the terminal duct lobular
units (TDLUs) of the breast have long been recognized by pathologists and have been described under a
wide variety of names
In the pre-mammographic era, columnar cell lesions were identified as
incidental microscopic findings in breast tissue removed because of other abnormalities and generally
received little attention. Recently, there has been renewed interest in these lesions since they are
being encountered with increasing frequency in breast biopsies performed because of the presence of
Some of these lesions feature banal columnar cells that are in
a single layer or show stratification and tufting, but without cytologic atypia or complex architectural
patterns. In others, the lining cells exhibit cytologic atypia, most commonly of the low-grade,
monomorphic type. Such lesions are now included within the category "flat epithelial atypia" (FEA)
Finally, some columnar cell lesions feature both cytologic atypia and complex architectural patterns.
The purpose of this article is to review the classification, diagnostic features, differential
diagnosis, and clinical significance of columnar cell lesions and flat epithelial atypia of the breast.
Classification and Diagnostic Features
Columnar cell lesions represent a morphologic spectrum that have in common the presence of enlarged
TDLUs composed of variably dilated acini that are lined by columnar epithelial cells, ranging from those
that show little or no cytologic or architectural atypia to those that show sufficient cytologic and
architectural features to warrant a diagnosis of atypical ductal hyperplasia (ADH) or ductal carcinoma in
The manner in which columnar cell lesions are classified has varied among different authors and the
classification of these lesions continues to evolve. We currently use a modification of the system
proposed by Schnitt and Vincent-Salomon . In this modification, columnar cell lesions are classified
as either columnar cell change, columnar cell hyperplasia, or flat epithelial atypia.
Columnar cell change represents the simplest of the columnar cell
lesions. These lesions are characterized by enlarged TDLUs with variably dilated acini that often have
an irregular contour. These acini are lined by one or two layers of columnar epithelial cells with
uniform, ovoid to elongated nuclei oriented in a regular fashion perpendicular to the basement membrane,
with evenly dispersed chromatin and without conspicuous nucleoli. Mitotic figures are rarely
encountered. Apical cytoplasmic blebs or snouts are often present at the luminal surface of the
epithelial cells but are not usually prominent or exaggerated. Flocculent secretions may be present in
the lumina of the involved acini. In addition, luminal calcifications may be present.
Columnar cell hyperplasia is characterized by enlarged TDLUs with
variably dilated acini which are often irregular in contour and are lined by columnar cells which have
cytologic features similar to those seen in columnar cell change but which, in addition, show cellular
stratification of more than two cell layers. Again, the nuclei are ovoid to elongated and, for the most
part, oriented perpendicular to the basement membrane. Crowding or overlapping of the nuclei in these
proliferative foci may give the appearance of nuclear hyperchromasia. The proliferating columnar cells
may form small mounds, tufts or abortive micropapillations. Exaggerated apical cytoplasmic snouts and
abundant flocculent intraluminal secretions are often present and some of the cells comprising such
lesions may have a hobnail appearance. These lesions frequently show intraluminal calcifications which
in some instances may have the configuration of psammoma bodies.
Some of the names that have been previously used to describe the lesions we now classify as columnar
cell change and/or columnar cell hyperplasia include columnar alteration of lobules , columnar
metaplasia(2}, blunt duct adenosis
columnar alteration with prominent apical snouts and
secretions(14), enlarged lobular units with columnar alteration (ELUCA)
and hyperplastic enlarged lobular units (HELU}
, among others.
In the classification previously proposed by Schnitt and Vincent-Salomon , lesions with
the architectural features described above for columnar cell change and columnar cell hyperplasia that
also exhibited cytologic atypia (usually of the low-grade, monomorphic type) were categorized as columnar
cell change with atypia and columnar cell hyperplasia with atypia, respectively. Since the proposal of
that classification system, the World Health Organization (WHO) Working Group on the Pathology and
Genetics of Tumours of the Breast  introduced the term flat epithelial
atypia (FEA) for lesions of the TDLUs in which the native epithelial
cells are replaced by one to several layers of cuboidal to columnar epithelial cells that show cytologic
atypia, most commonly of the low grade or monomorphic type. Thus, lesions previously categorized by
Schnitt and Vincent-Salomon as columnar cell change with atypia and columnar cell hyperplasia with
atypia  would be included in the WHO category of FEA. Given that FEA is the term proposed by the WHO
Working Group, we believe that for the purpose of standardization it is prudent for pathologists to use
this term for these lesions and we have adopted this approach in our clinical practice. It is important
to note that lesions currently included within the category of FEA have previously been described by a
wide assortment of other names, most notably "clinging carcinoma" of the monomorphic type
The cuboidal to columnar epithelial cells comprising FEA most often show low grade cytologic atypia
characterized by the presence of relatively monomorphic, round to ovoid nuclei that resemble those seen
in the cells comprising low grade ductal carcinoma in situ . These nuclei are not regularly oriented
perpendicular to the basement membrane and show an increase in the nuclear/cytoplasmic ratio. As a
result of this increased nuclear/cytoplasmic ratio, the involved TDLUs typically have a more basophilic
(bluer) appearance than normal TDLUs at scanning magnification. Cellular and nuclear stratification is
seen in some cases. The nuclear chromatin may be evenly dispersed or slightly marginated and nucleoli
are variably 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 tubules of tubular carcinoma. In a minority of cases of FEA, the nuclei retain a more
oval shape as well as orientation perpendicular to the basement membrane. However, in contrast to the
relatively slender, bland nuclei of columnar cell change and columnar cell hyperplasia, the chromatin in
these nuclei may show clumping and margination, nucleoli are variably prominent, and the
nuclear/cytoplasmic ratio of the cells is markedly increased.
The epithelial cells in FEA lesions may form small mounds, tufts or short, abortive
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 within the micropapillations and bars or around the fenestrations, are absent.
Thus, it should be apparent that "flat" is a relative term, simply denoting the absence of the complex
architectural patterns described above. These lesions also frequently show intraluminal calcifications
which in some instances may have the configuration of psammoma bodies. A variable lymphocytic infiltrate
may be present in the stroma surrounding spaces involved by FEA.
Columnar cell change, columnar cell hyperplasia, and FEA may co-exist in the same breast and even
within the same terminal duct lobular unit. Therefore, these diagnoses should not be considered mutually
It is important to recognize that high grade cytologic atypia with marked nuclear pleomorphism of the
type seen in high grade DCIS is not a feature of lesions included in the category of FEA . The
presence of such high grade nuclear features merits the designation of high grade DCIS, even if the cells
comprise only a single cell layer . However, such lesions are rarely seen in the absence of high
grade DCIS exhibiting other architectural patterns.
Some lesions composed of columnar epithelial cells show more complex architectural
patterns such as well-developed micropapillations, rigid cellular bridges, bars and arcades, or
punched-out fenestrations, with at least some evidence of cellular polarization within the
micropapillations and bars or around the fenestrations. It has been suggested that such lesions be
categorized as columnar cell hyperplasia with moderate or severe atypia  or as columnar cell
hyperplasia with architectural atypia or with architectural and cytologic atypia . However, we
believe that for practical purposes, it is most prudent to categorize such lesions as either ADH or DCIS,
depending upon the severity and extent of the combined cytologic and architectural features .
The ability of pathologists to reproducibly distinguish non-atypical columnar cell lesions
(i.e., columnar cell change and columnar cell hyperplasia) from FEA is a matter of legitimate concern.
This issue has been addressed in several recent studies. In one study, 6 breast pathologists reviewed
histologic slides from 30 columnar cell lesions and were asked to employ the criteria they use in their
routine practice to classify the lesions and to report the presence or absence of atypia. Under these
conditions, all 6 participants agreed on the presence of cytologic atypia in only 40% of the cases, and
the kappa value for the identification of cytologic atypia was 0.34, indicating only "fair" agreement
. In another study, by O'Malley et al, 8 pathologists with expertise in breast pathology reviewed
digital images of 30 examples of columnar cell lesions and FEA and were asked to categorize each lesion
as either "not atypical" or as "FEA". In contrast to the study of Mohsin, the pathologists in the
O'Malley study were first provided with a written set of diagnostic criteria as well as tutorial
illustrating examples of the various columnar cell lesions . The level of agreement observed in this
latter study was remarkably high. Overall agreement among the 8 pathologists was 91.8% and the
multi-rater kappa value was 0.83, which is in the "excellent agreement" range. While these results
suggest that the distinction of FEA from columnar cell lesions without atypia is highly reproducible with
the use of standardized diagnostic criteria, another recent report did not find a similarly high level of
agreement in the recognition of atypia in columnar cell lesions after study of a training tutorial by the
participating pathologists . Thus, achieving consensus in the identification of cytologic atypia in
columnar cell lesions remains an important goal.
The majority of the cells comprising both columnar cell lesions and FEA exhibit expression
of cytokeratin 19
and most if not all of these cells lack expression of high molecular weight
cytokeratins (HMW-CK) as defined by antibody 34ßE-12 and antibodies to cytokeratin 5 or 5/6
The practical implication of the latter observation is that absence of HMW-CK expression cannot be used
as an objective marker of atypia in columnar cell lesions, as it has been used to distinguish 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)
Columnar cell lesions and FEA typically exhibit intense nuclear expression of estrogen receptor
and progesterone receptor
in the majority of the cells. With regard to cell cycle
and proliferation markers, in one study of columnar cell lesions 5% to 50% of the cells stained for
cyclin D1 . In another study, 75% of the columnar cell lesions studied show no nuclear staining for
the Ki-67 antigen and the remainder of the cases showed only rare Ki-67-positive cells, indicating that
the cells comprising columnar cell lesions, even those with atypia, have a low proliferative rate .
Overall, however, the cells comprising columnar cell lesions appear to have a higher proliferation rate
and less apoptosis than normal TDLUs .
The cells comprising columnar cell lesions and FEA also show strong cytoplasmic expression of the
anti-apoptic protein bcl-2 .
Recent studies have begun to investigate the genetic alterations in columnar cell lesions. In a study
of 13 cases of "DIN-flat monomorphic type" (FEA),
Moinfar et al  found that 70% showed loss of
heterozygosity (LOH) at one or more of the eight loci evaluated and further, that the genetic alterations
in these columnar cell lesions were the same as those in the associated DCIS or invasive cancer. In that
study, the most common losses were at 3p and 11q, but losses were also seen at 2p, 16q, and 17q.
Moreover, both cases in which clonality was assessed using an X chromosome inactivation assay were found
to be monoclonal. 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. In that study, chromosomal alterations were found in
7 of 10 cases of FEA, but also in 10 of 14 examples of columnar cell change and 9 of 11 examples of
columnar cell hyperplasia. While the genomic changes were relatively few in number in all categories and
were identified on multiple chromosomes, recurrent losses on 16q, 17p and X, and gains of 15q, 16p and 19
were observed across the spectrum of columnar cell lesions and FEA. In addition, in 5 of 8 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. Most recently, Dabbs et al  studied the
spectrum of columnar cell lesions for LOH at 10 loci. LOH was not detected in either of two examples of
columnar cell change. In contrast, losses at one of more loci were seen in 2 of 3 examples of columnar
cell hyperplasia and 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.
Columnar cell change, columnar cell hyperplasia and FEA are all characterized by TDLUs
with enlarged, dilated acini containing variable amounts of secretory material. Therefore, all of these
lesions may be mistaken for microcysts on scanning magnification. Examination of the dilated acini at
higher power will reveal the columnar nature of the lining epithelial cells, distinguishing these lesions
from non-apocrine microcysts which are typically lined by attenuated, cuboidal epithelium. In addition,
higher power examination will reveal the cytologic atypia that characterizes FEA and that represents the
cardinal feature that distinguishes this lesion from both columnar cell change/hyperplasia and
microcysts . The features useful in making the distinction between columnar cell change, columnar
cell hyperplasia and FEA from each other are provided in Table 2. In our view, however, 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.
Columnar cell change, columnar cell hyperplasia and FEA must also be distinguished from benign
apocrine lesions such as apocrine metaplasia and apocrine hyperplasia. Although the cells comprising
columnar cell lesions, FEA and apocrine lesions may all feature apical cytoplasmic snouts, the cells of
apocrine lesions possess more abundant, granular, eosinophilic cytoplasm than those of these other
lesions. In addition, the nuclei of apocrine lesions tend to be round and have a single prominent
nucleolus. Furthermore, whereas hobnail type cells and highly exaggerated apical snouting are seen in
some columnar cell lesions and FEA, they are not seen in apocrine lesions. Finally, in contrast to the
cells of columnar cell lesions and FEA which typically show strong expression of estrogen receptor and
bcl2, apocrine epithelial cells characteristically lack expression of both of these proteins .
When columnar cell lesions become more proliferative, the differential diagnostic considerations
include usual ductal hyperplasia, atypical ductal hyperplasia and ductal carcinoma in situ. Columnar
cell hyperplasia may have areas that begin to mound up into broad based tufts raising the differential
diagnosis with usual ductal hyperplasia. While the pronounced columnar nature of the cells and the
pencillate nuclei favor columnar cell hyperplasia over usual ductal hyperplasia, making this distinction
is of questionable diagnostic importance. As noted earlier, we believe that it is most prudent to
categorize columnar cell lesions that show both cytologic atypia and complex architectural patterns as
either ADH or DCIS, depending upon the severity and extent of the cytologic and architectural
Columnar cell lesions with cytologic atypia in which the features do not possess
the combined cytologic and architectural criteria for ADH and DCIS are best classified as FEA.
It is difficult to assess the clinical significance of columnar cell lesions due to variations in the
terminology used to describe these lesions and the limited number of cases that have been studied in a
systematic fashion. Nonetheless, several observational studies have clearly shown that the lesion now
recognized as FEA commonly co-exists with well developed examples of ADH, low-grade DCIS and tubular
carcinoma and that the cells comprising the FEA share cytologic and immunophenotypic features with the
cells comprising these other lesions
A number of authors have also noted an
association between columnar cell lesions/FEA and lobular neoplasia (lobular carcinoma in situ and
atypical lobular hyperplasia)
Based on the foregoing observations, in conjunction with the recent genetic data cited earlier, it is
reasonable to conclude that at least some columnar cell lesions, particularly FEA, are neoplastic
proliferations that may well represent either a precursor to, or the earliest morphologic manifestation
of, low grade DCIS as well as a precursor to invasive carcinoma, particularly tubular carcinoma. While
this is of great interest from a biological point of view, the clinical implications of these
observations can only be determined from follow-up studies. Unfortunately there are only a few studies
to date that have addressed the clinical significance of these lesions.
In a follow-up study of 3303 women with benign breast biopsies, Page et al reported a 1.3-fold
increase in breast cancer risk among women whose biopsies showed columnar cell change (a lesion which in
that study was designated atypical lobules A and which was later termed enlarged lobular units with
columnar alteration, ELUCA)
In a subsequent case-control study of 248 women (82 cases and 166
controls) nested within this cohort, McLaren et al noted that the risk of breast cancer among women in
whom the ELUCA lesions failed to express ER was almost twice that of those with ER-positive ELUCA
In another study, Shaaban et al performed a case-control study of almost 700 patients to determine
the relationship between various benign breast lesions and the risk of subsequent breast cancer . The
median follow-up period was 5.5 years. In that study, columnar cell lesions (which they referred to as
blunt duct adenosis, BDA) were divided into six sub-groups (BDA, NOS; BDA with calcifications; BDA with
columnar cell metaplasia; BDA with atypical columnar cell metaplasia; BDA with hyperplasia of the usual
type; and BDA with ADH). While the finding of blunt duct adenosis, NOS was associated with about a
2-fold increase in breast cancer risk, no other subgroup of columnar cell lesions was significantly
associated with the subsequent development of breast cancer (including those with atypia). However,
given that the number of patients in some of these subgroups was quite small and the follow-up period in
this study was relatively short, the clinical significance of these findings is not clear.
To date, there have been three follow-up studies that provide information regarding the outcome of
patients with FEA. In a review of over 9000 breast biopsies that were initially considered benign,
Eusebi et al retrospectively identified 25 patients with so-called "clinging carcinoma" of the flat,
monomorphic (low nuclear grade)
(lesions now included in the FEA category). Only one of these
patients (4%) developed a "local recurrence" after an average follow-up period of 19.2 years. However,
the "local recurrence" in this patient consisted of a "clinging carcinoma" lesion histologically
identical to the original lesion, and it is not possible to determine whether this simply reflected
persistence of the original lesion due to inadequate excision or a true local recurrence. Of note, none
of these 25 patients developed an invasive breast cancer within the follow-up period. In another study,
59 patients with "clinging carcinoma" of the low nuclear grade type were identified among the patients
entered into the European Organization for Research and Treatment of Cancer (EORTC) 10853 study, a
randomized clinical trial comparing excision and radiation therapy and excision alone for the treatment
of women with DCIS . There have been no local recurrences among those 59 patients with a median
follow-up of 5.4 years. Most recently, de Mascarel et al studied 115 patients with FEA who had been
treated with surgical excision alone (n=70) or a surgical excision plus radiation therapy (n=45)
With a median follow-up of 13.3 years, 3 patients (2.6%) developed recurrent FEA in the ipsilateral
breast and 3 (2.6%) developed ipsilateral invasive breast cancer 1, 7 and 12 years after the original
diagnosis of FEA (2 following surgical biopsy alone and 1 following surgical biopsy and radiation
Taken together the results of these studies suggest that despite the morphologic, immunophenotypic,
and genetic similarities between the cells of FEA and those of fully developed examples of low-grade
DCIS, the risk of progression of FEA to invasive cancer appears to be extremely low when present as an
isolated lesion. Additional clinical follow-up studies are needed to better understand the relationship
between these lesions and the risk of subsequent breast cancer.
Pathology Work-Up and Management Recommendations
The appropriate pathology work-up and clinical management of patients whose biopsy specimens show
columnar cell lesions and FEA are evolving as information regarding these lesions accumulates.
Core Needle Biopsy
The limited available data suggest that neither additional pathology work-up nor excision are required
when either columnar cell change or columnar cell hyperplasia are encountered in a CNB specimen
In contrast, recent data have suggested that when FEA is encountered in a CNB specimen, subsequent
excision shows a more advanced lesion in about one-quarter to one-third of cases, which is sufficiently
frequent to recommend excision as a matter of routine in such cases
There are no data to suggest that the presence of columnar cell change or columnar cell hyperplasia in
an excisional biopsy specimen requires further pathologic evaluation or additional treatment. However,
the presence of FEA in an excisional biopsy specimen should prompt a careful search for areas with
diagnostic features of ADH or DCIS by obtaining additional levels from the block or blocks containing the
lesion and by the submission of the remainder of the tissue for histological examination.
There are several other considerations regarding FEA in excisional biopsy specimens that merit
discussion. When a proliferation that fulfills the diagnostic criteria for ADH or DCIS is found to arise
in a background of FEA, it seems most prudent to manage the patient as one would manage ADH or DCIS in
any other setting. However, there are two issues that remain to be resolved when FEA is found to
co-exist with diagnostic areas of DCIS, particularly in cases in which the cytologic features of the
cells comprising the FEA are similar or identical to those of the cells comprising the diagnostic areas
of DCIS. The first is whether or not the FEA should be taken into consideration in determining the size
or the extent of the DCIS lesion, and the second is whether or not the presence of FEA at the excision
margins is sufficient to consider the margins "positive," requiring further surgical resection. Given
that the available clinical data, albeit limited, suggest that FEA is associated with a very low risk of
recurrence or progression to invasive carcinoma, we believe these lesions should not be taken into
consideration when determining the size of a co-existent DCIS lesion or in the evaluation of the status
of the margins of excision, even when composed of cells that are cytologically similar to those in the
diagnostic areas of DCIS.
Another increasingly common problem is the management of patients whose breast biopsies, after
thorough examination, show FEA without diagnostic areas of ADH or DCIS. Again, we would argue that
despite the fact that these lesions may well be composed of cells that are identical to those seen in
some forms of DCIS, the few available clinical follow-up studies of these lesions suggest that they are
associated with a risk of subsequent breast cancer that is considerably lower than that seen with fully
developed forms of low grade DCIS. Therefore, managing patients with such lesions as if they had DCIS
would result in overtreatment of many patients.
Columnar cell lesions and FEA are being encountered with increasing frequency in breast biopsies
performed because of mammographic microcalcifications. 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 define better the relationships of various columnar
cell lesions to each other and to DCIS and invasive breast cancer. Emerging data suggest that lesions
categorized as FEA are neoplastic, clonal proliferations that may represent a precursor to or the
earliest form of low grade DCIS. Despite this, the limited available clinical follow-up data suggest
that the risk of progression of these lesions to invasive cancer appears to be 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. Nevertheless, the identification of FEA in a breast
biopsy should serve as a "red flag" alerting the pathologist to the possible presence of co-existing ADH,
DCIS, lobular neoplasia and invasive carcinoma (particularly tubular carcinoma), lesions about which
clinical management strategies are better defined.
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