Columnar cell lesions of the breast
Columnar cell breast lesions result from changes in the configurations of columnar cells occuring right in and around the terminal duct lobular unit (TDLU) of the breast. It must be stressed from the very beginning that discussions about the various different types of columnar cell breast lesions are more of a concern for breast cancer researchers than for women in the general population, or even women undergoing breast cancer screening.
I just want to let you know that I have a newer version of this page with more up-to-date information on Columnar Cell Lesions of the Breast. However, even though this page is a little bit old, it still has very useful material, and I would still use it.
Columnar cells are epithelial cells which have an elongated shape with a height about 4 times the width. Columnar cells are a normal part of functional breast ducts and TDLU’s, but sometimes they develop in unusual ways, or grow more rapidly than one would expect.
But if a women and a physician are talking about columnar cell lesions at all, in all likelihood following a breast cancer screening mammogram and subsequent microscopic analysis of a fine needle aspiration tissue sample, it means that there is either absolutely nothing to worry about, or if there is anything potentially worrisome, it has been identified at the earliest possible stage, in fact, too early to even warrant further investigation let alone treatment.
And, if by chance a columnar cell lesion were after some time to develop into something resembling ductal carcinoma in situ, it would be picked up and treated before developing into anything serious.
Columnar cell change (CCC), columnar cell hyperplasia (CCH) and flat epithelial atypia (FEA)
There is no consistent ‘international standard‘ for naming columnar cell breast lesions, but essentially they are named according to the number of layers of columnar cells present, and whether or not these cells have any atypical features. The term “Columnar Cell Change” is basically a simple, single layer of columnar cells lining a lobule, while ‘Columnar Cell Hyperplasia‘ refers to two or more layers of columnar cells (hyperplasia means excessive growth of a particular cell type, but still a cell that is normally found in the area).
The term flat epithelial atypia (FEA) may or may not be included within the group of columnar cell lesions, but probably should. It refers specifically to a ‘flat‘ pattern of probably 2 layers of columnar cells lining a lobules, and in which many cells have atypical features. (When hyperplastic cells have atypical features, many cancer researchers prefer to consider them under the category of atypical ductal hyperplasia instead).
Columnar cells breast lesions usually accompany microcalcifications found on a breast cancer screening mammogram
A columnar cell lesion of the breast is usually discovered by a breast cancer screening mammogram, and in particular by the presence of microcalcifications. About 75% of breast columnar cell lesions will show microcalcifications, and they usually have a round or pleomorphic appearance, and a small number (about 10% to 11%) will show branching microcalcifications.
Columnar cell lesions are typically associated with calcifications of the calcium phosphate type, and they become deposited within the variably sized duct lumina of dilated terminal duct lobular units. In fact, in terms of all mammographic findings associated with breast calcifications, columnar cell alterations rank fifth, following breast fibrocystic change, breast fibroadenoma, then ductal carcinoma in situ (DCIS) and finally sclerosing adenosis.
So with columnar cell breast lesions, after microcalcifications are discovered in either amorphous or clustered distributions on the screening mammogram, an analysis of a subsequent fine needle aspiration tissue sample will tend to show these various small cystic lobules lined with columnar cells, either in a single layer (simple), or in multiple layers (stratified).
If there is any concern it all, it will tend to be founded upon any ‘atypical‘ appearance to the columnar cells.
Other common names for columnar cell breast lesions
A columnar cell breast lesion occurs when breast terminal duct epithelium assumes a columnar morphologic appearance. This type of breast tissue development has been given a number of different names over the years, such as columnar alteration with prominent apical snouts and secretions (CAPSS), abnormal involution, cystic lobules, atypical cystic lobules, atypical lobules, hyperplastic lobules, hyperplastic unfolded lobules, and enlarged lobular units with columnar alteration.
Other names for the condition have included ‘columnar alterations of lobules‘, columnar metaplasia, enlarged lobular units with columnar alteration, hyperplastic unfolded lobules, hyperplastic enlarged lobular units , and even blunt duct adenosis.
There are basically two categories of breast columnar cell lesions
But essentially there are two categories of columnar cell breast lesions; Columnar Cell Change, in which a single layer of columnar cells lines a breast lobule, and Columnar Cell Hyperplasia, in which two or more layers of columnar cells have developed lining a lobule. Each of these two basic categories has a ‘with atypica‘ qualifier, and these are the ones that are possible more suspicious for development of atypical ductal hyperplasia or ductal carcinoma in situ.
In a broad sense, the atypical categories of columnar cell lesions might really be viewed as a subcategory of atypical duct epithelial hyperplasia (ADH).
Certain kinds of columnar cell breast lesions (Flat epithelial atypica) may be associated with very early breast cancer development (ductal carcinoma in situ)
Some breast cancer researchers feel that there is a spectrum of change in the various presentations of columnar cell lesions which might imply an associated progression towards atypia and ultimately to ductal carcinoma. This is not a universally agreed-upon idea, but one can understand how breast cancer research will tend to look for the earliest ‘formative‘ conditions of breast carcinoma, in hopes of finding a cure or altering the potential disease course.
But we are reminded that the very early columnar cell changes discussed here would only be revealed through breast cancer screening, and in most cases the follow up advice will be simply to observe the situation.
Atypical features of columnar cell breast lesions
Atypical cellular features of columnar cell lesions may present as ‘flat atypia‘ which likely represents a morphologic form of atypical duct epithelial hyperplasia. Flat epithelial atypia is cytologically a higher-grade atypia but without abundant epithelial proliferation.
There is a general feeling that flat epithelial atypia is a more serious finding which might have a greater chance to develop into something potentially worrisome for breast cancer, so women showing FEA within a columnar cell breast lesion will probably have a more rigorous diagnostic work up and shorter follow-up. About one-third of follow-up excisions of flat epithelial atypia show a more serious pathology, which is about the same rate of ‘serious‘ incidence in excisional follow-up of atypical duct epithelial hyperplasia.
In the few instances where a connection has been made between atypical columnar cell hyperplasia or flat epithelial atypia with ductal carcinoma in situ (DCIS), the most common DCIS seen is a low grade micropapillary/cribriform type.
Atypical cystic lobules may signal and early phase DCIS
Other breast cancer studies have noted the close geometric proximity of cystic lobules of columnar type, atypical proliferations and DCIS, and have suggested that the atypical cystic lobules in atypical columnar cells breast lesions may be an early phase in the evolution towards DCIS.
Overall Histological aspects of Columnar Cell breast lesions
Microscopic analysis of suspected columnar cell breast lesions will tend to reveal a transformation of the terminal duct-lobular unit from a low cuboidal epithelium to a tall columnar epithelium, and it will often be cystically dilated to some degree. This new, altered cell type in the TDLU,(columnar cell change) may be associated with breast lobules of a normal size, lobules which are enlarged, or lobules with are both enlarged and dilated.
After this initial ‘columnar cell change‘ phase, an epithelial thickening or ‘piling up‘ in the form of hyperplasia might follow. If there are atypical aspects, they may manifest either as oddly shaped cells or nuclei and other cytological atypia (such as staining evidence for certain proteins), or they may exhibit architectural atypia in the form of either ‘roman arches‘ or ‘club-shaped‘ micropapillae.
Columnar cell breast lesions tend to be ER and PR positive, with other unique immunochemical markers
Columnar cell breast lesions tend to be ER and PgR positive, but CK5/6 and CK14 negative. Markers for bcl-2 and Cyclin D are also prominent in many columnar cell lesions of the breast. Cyclin D is a member of the cyclin family of cell cycle regulators. These proteins are expressed in a semi-redundant, overlapping fashion in most proliferating cells and collectively they regulate the progression of cells through the cell cycle.
Increased Ki-67 indices, cyclin D1 expression and anti apoptosis signaling with bcl-2 give supporting evidence for accelerated growth fractions of proliferative and atypical columnar alterations. The elevated up regulation of ER suggests that columnar cell alterations in the breast TDLU’s might possibly escape normal ER regulation, and might even represent a potential avenue to an ER-dependent breast carcinoma development.
Cytologic features of Breast Columnar Cell Change (CCC)
Columnar Cell Change is the simplest from of columnar cell breast lesions, and is generally characterized by enlarged terminal duct lobular units with variably dilated acini, and possibly with an irregular contour. Breast columnar cell change lesions will tend to have one to two layers of columnar epithelial cells with uniform ovoid nuclei, which are oriented perpendicular to the basement membrane. There are generally no conspicuous nuclei in breast CCC lesions.
It is quite common for apical cytoplasmic blebs, or snouts, to be present at the luminal surface of the cells. Flocculent (fluffy or wooly) secretions might also be present in the lumina of the acini. (Both apocrine metaplasia and breast columnar cell change are characterized by apical snouts, but in apocrine metaplasia the cytoplasm is much more abundant and eosinophilic).
Sometimes a fine needle aspiration sample of a columnar cell change lesions might at first give a worrying pattern, because columnar cells tend to disperse and appear as single cells on smears.
Columnar Cell Change breast lesions are frequently accompanied by microcalcifications, which are often very fine, and may either be luminal, intra-epithelial, or in the adjacent stroma. Oxalate calcifications are very uncommon.
Cytologic features of Breast Columnar Cell Hyperplasia
Breast columnar cell hyperplasia (CCH) is similar to CCC in that it tends to demonstrate enlarged TDLU’s, also with variably dilated acini and often irregular contours. The main difference is that breast columnar cell hyperplasia features stratification of more than two layers of columnar cells, sometimes forming mounds or tufts with exaggerated apical snouts. Luminal secretions tend to be abundant with breast columnar cells hyperplasia, as well as microcalcifications.
The image of breast columnar cell hyperplasia shown below demonstrates enlarged terminal duct lobular units containing calcifications.
Nuclei in breast columnar hyperplasia cells tend to be round or ovoid, and are oriented perpendicular to the basement membrane. Overlapping and crowding of nuclei are also common.
Flat Epithelial Atypia (FEA) of the breast
The columnar cell breast lesion now known as Flat epithelial atypia (FEA) was first described as ‘clinging carcinoma‘. Flat epithelial atypia does not always occur on its own, but may coexist with atypical ductal hyperplasia (ADH), DCIS, and tubular breast carcinoma.
The presence of Flat Epithelial atypia on a fine needle biopsy generally results in a more thorough excisional or core biopsy in search of either atypical ductal hyperplasia or DCIS. A more advanced or serious breast neoplasm is found in about one third of flat epithelial atypia core biopsies, either ADH, DCIS, or very rarely, tubular breast carcinoma.
Breast flat epithelial atypia and these other lesions have similar atypical cytologic and immunophenotypic features, and for this reason some breast cancer physicians consider FEA to be a ‘neoplastic proliferation‘ that might represent either a precursor to or the earliest morphologic manifestation of low-grade DCIS.
However, any breast carcinoma associated with flat epithelial atypia tends to be of a very low nuclear grade. When present, the DCIS associated with columnar cell lesions is of a low grade about 55% of the time, while high grade DCIS is only reported about 20% of the time.
Risk of local recurrence is low
The risk of local recurrence of flat epithelial atypia is very low, at around 2.5%, and the risk of FEA actually progressing to invasive breast cancer (following intervention) is even lower, in spite of certain histologic and genetic similarities that might exist between flat epithelial atypia and DCIS.
Cytologic features of flat epithelial atypia
Microscopically, flat epithelial atypia is characterized by enlarged terminal duct lobular units with variably dilated acini, which also tend to be rounded and basophilic. FEA breast lesions typically consist of one or more layers of columnar or cuboidal epithelial cells, and with cytologic atypia and apical snouts that might be exaggerated. Unlike columnar cell hyperplasia, the nuclei of flat epithelial atypia are not oriented perpendicular to the basement membrane.
Columnar cells tend to show low-grade cytologic atypica, with nuclei are generally monomorphic and round or oval in shape. Chromatin in the nucleus tend to show margination and clumping, variably prominent nucleoli, and a marked increase in the nucleus-to-cytoplasm ratio. As a result, the TDLU’s with flat epithelial atypia tend to have a more basophilic appearance than ‘non-atypical‘ columnar cell breast lesions.
The image of flat epithelial atypica of the breast show below shows multiple layers of epithelial cells with cytologic atypia lining the duct.
Flat epithelial atypia of the breast has been referred to previously by a variety of names, including atypical cystic lobules, clinging carcinoma (monomorphic type), atypical columnar cell breast lesions, atypical cystic ducts, CAPPS with atypica, breast columnar cell change with atypia, and breast columnar cell hyperplasia with atypia.
Microcalcifications common to flat epithelial atypia
Breast flat epithelial atypia lesions tend to feature morphous and fine pleomorphic microcalcifications. Sometimes intraluminal calcifications have the appearance of psammoma bodies. Psammoma bodies are calcifications with an unusual (and quite pretty) lamellar pattern.
Columnar Cell Breast Lesions demonstrate Loss of Heterogeneity
Recent studies regarding the molecular and genomic features of columnar cell breast lesions have demonstrated some consistencies when compared with ‘confirmed‘ worrisome or potentially pre-cancerous lesions such as atypical ductal hyperplasia.
One noted finding is the ‘loss of heterozygocity‘ (LOH) in both typical and atypical columnar cell breast lesions, and low numbers in certain genes such as 16q, and also 17p, 17q, 9q, and 10q. Molecular abnormalities including loss of heterogeneity have been observed in between 40%-55% of both usual and atypical epithelial hyperplasia (the LOH rate for atypical hyperplasia is higher, but just slightly).
This does suggest a strong possibility that molecular abnormalities observed in epithelial hyperplasia (including breast columnar cell hyperplasia) progressively accumulate into the kinds of breast lesions that are presently recognized as ductal carcinoma in situ.
Conclusions about columnar cell lesions of the breast
If one does internet-based research about columnar cell breast lesions, it is possible to get a mistaken impression that they are a big deal. Remember that a certain element of breast cancer research will always be oriented towards molecular and genetic discoveries at the very earliest, even undifferentiated stage of cells. If they can figure out what genetic features and context support the growth of mutating cancer cells, that probably holds the best hope for finding a cure.
So, it follows that breast cancer researchers will focus great attention on any kind of ‘atypical‘ cell features of formations. And, within the context of breast columnar cell lesions, a certain small percentage of them will show atypical features, and a certain small percentage of those may evolve into atypical ductal hyperplasia, and a certain small percentage of those cells might possible evolve into ductal carcinoma in situ.
The most important thing for a woman who has been told she has ‘columnar cell hyperplasia‘ following a breast cancer screening, is that in the rare instance that a potentially worrisome ‘atypical‘ features is detected, it is almost certain that the lesion will be excised, contained, and cured.
If breast columnar cell change of columnar cell breast hyperplasia is identified via a percutaneous breast biopsy, the next step is clinical follow-up in about a year, rather than surgical excision. With flat epithelial atypia, which is thought to be a little bit more serious, the entire lesion might be excised, either right away or after a short observation period.
Atypical columnar cell lesions of the breast are not a significant concern
What the research is suggesting about atypical columnar cell breast lesions is that there may be a logical continuum from columnar cell change, to columnar cell hyperplasia, to CCC and CCH with atypia, to flat epithelial atypia, to atypical ductal hyperplasia, and to ductal carcinoma in situ.
Recent molecular/genomic data does support a hypothesis that some columnar cell breast lesions (those with atypia) might be a non obligate, intermediary step in the development of some forms of low grade in situ and invasive breast carcinoma, but even so, its not going to cause a patient any problems of significance when discovered (and hence discussed) at such an early stage.
For further reading, I suggest you visit this page on columnar cell mucinous carcinoma of the breast, also known as mucinous cystadenocarcinoma (MCA)
- Simpson PT, Gale T, Reis-Filho JS, Jones C, Parry S, Sloane JP, Hanby A, Pinder SE, Lee AH, Humphreys S, Ellis IO, Lakhani SR. Columnar cell lesions of the breast: the missing link in breast cancer progression? A morphological and molecular analysis. Am J Surg Pathol. 2005 Jun;29(6):734-46.
- Nährig J. Practical problems in breast screening. Columnar cell lesions including flat epithelial atypia and lobular neoplasia. Pathologe. 2008 Nov;29 Suppl 2:172-7.
- Schnitt SJ, Vincent-Salomon A. Columnar cell lesions of the breast. Adv Anat Pathol. 2003 May;10(3):113-24.
- Nasser SM.Columnar cell lesions: current classification and controversies. Semin Diagn Pathol. 2004 Feb;21(1):18-24.
- Pandey, S., Kornstein, J., Shank, W., de Parades, ES. Columnar Cell Lesions of the Breast: Mammographic Findings with Histopathologic Correlation. RadioGraphics,(October 2007) 27, S79-S89.
- Schnitt SJ, Collins LC. Columnar cell lesions and flat epithelial atypia of the breast. Semin Breast Dis 2005; 8: 100–111.
- FraserJL, Raza S, Chorny K, et al. Columnar alteration with prominent apical snouts and secretions: a spectrum of changes frequently present in breast biopsies performed for microcalcifications. Am J Surg Pathol 1998; 22: 1521–1527.
- PageDL, Kasimi M, Jensen RA. Hypersecretory hyperplasia with atypia in breast biopsies: what is the proper level of clinical concern? Pathol Case Rev 1996; 1: 36–40
- BijkerN, Peterse JL, Duchateau L, et al. Risk factors for recurrence and metastasis after breast-conserving therapy for ductal carcinoma-in-situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853. J Clin Oncol 2001; 19: 2263–2271.
- de MascarelI, MacGrogan G, Picot V, et al. Results of a long term follow-up study of 115 patients with flat epithelial atypia [abstr]. Lab Invest 2006; 86(suppl 1): 25A.
- MohsinS, Badve S, Bose S, et al. Assessment of variability in diagnosing “atypia” in columnar cell lesions (CCL) of the breast. Lab Invest 2005; 85(suppl 1): 44A.
- DabbsDJ, Carter G, Fudge M, et al. Molecular alterations in columnar cell lesions of the breast. Mod Pathol 2006; 19: 344–349.
- BrogiE, Tan LK. Findings at excisional biopsy (EBX) performed after identification of columnar cell change (CCC) of ductal epithelium in breast core biopsy (CBX) [abstr]. Mod Pathol 2002; 15: 29A–30A.
- Roylance R, Gorman P, Papior T, Wan YL, Ives M, Watson JE, Collins C, Wortham N, Langford C, Fiegler H, Carter N, Gillett C, Sasieni P, Pinder S, Hanby A, Tomlinson I. A comprehensive study of chromosome 16q in invasive ductal and lobular breast carcinoma using array CGH. Oncogene. 2006 Oct 19;25(49):6544-53.
- Tan, PH., Ho, BCS, Selvarajan, S., Yapo, WM., Hanby, A., Pathological diagnosis of columnar cell lesions of the breast: are there issues of reproducibility? J Clin Pathol 2005;58:705-709
- Foote FWJ, Stewart FW. Comparative studies of cancerous vs. noncancerous breasts. Basic morphologic characteristics. Ann Surg 1916;12:6–53.
- Oyama T, Iijim K, Takei H, et al. Atypical cystic lobule of the breast: an early stage of low grade ductal carcinoma in-situ. Breast Cancer 2000;7:326–331.
- Rosen PP. Columnar cell hyperplasia is associated with lobular carcinoma in situ and tubular carcinoma. Am J Surg Pathol 1999;23:1561.
- Larson PS, de las Morenas A, Bennett SR, Cupples LA, Rosenberg CL. Loss of heterozygosity or allele imbalance in histologically normal breast epithelium is distinct from loss of heterozygosity or allele imbalance in co-existing carcinomas. Am J Pathol. 2002 Jul;161(1):283-90.
- Kerangueven F, Noguchi T, Coulier F, Allione F, Wargniez V, Simony-Lafontaine J, Longy M, Jacquemier J, Sobol H, Eisinger F, Birnbaum D: Genome-wide search for loss of heterozygosity shows extensive genetic diversity of human breast carcinomas. Cancer Res 1997, 57:5469-5474
- Washington C, Dalbegue F, Abreo F, Taubenberger JK, Lichy JH: Loss of heterozygosity in fibrocystic change of the breast: genetic relationship between benign proliferative lesions and associated carcinomas. Am J Pathol 2000, 157:323-329
- O’Connell P, Pekkel V, Fuqua SA, et al. Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. J Natl Cancer Inst 1998;90:697–703.
- Kaneko M, Arihiro K, Takeshima Y, et al. Loss of heterozygosity and microsatellite instability in epithelial hyperplasia of the breast. J Exp Ther Oncol 2002;2:9–18.
- Takahashi-Yanaga F, Sasaguri T. (April 2008). “GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy.”. Cell Signal. 20(4): 581–9.