It is for good reason that columnar cell lesions have recently become a highly controversial area in breast pathology. Over the past few years there has been an abundance of evidence firmly linking them to atypical hyperplasias, lobular pattern more so than ductal pattern, and the special type of mammary carcinoma, tubular carcinoma. This association was probably earliest to be noted by Goldstein and O’Malley,22
though their proposed designation and pathobiology of cancerization has proven to be inaccurate.
As elegantly tabulated by Abdel-Fatah,14
this non-random association has been supported by several studies that have shown significant overlap in the molecular alterations seen in both tubular carcinoma and CCA, bringing forth the idea that the atypical CCL may well represent a precursor state, not only for patterns of atypical hyperplasia, but also for low-grade special type (tubular) invasive carcinoma.
Despite these compelling findings, the available outcome studies that looked at CCA have failed to detect a significant risk for subsequent cancer on long-term follow-up. The first available study was by Eusebi and colleagues29
who retrospectively identified 21 patients with so-called "clinging carcinoma" of the flat, monomorphic type out of 4,000 benign breast biopsies performed between 1965 and 1971. After an average follow-up period of 19.2 years, only one of the patients had recurrence of a histologically identical lesion without evidence of DCIS or invasive tumor. Also, Bijker and colleagues,27
within the EORTC cancer trial, reported no local recurrence in 59 patients with, again so-called clinging carcinoma, after an average follow-up of 5.4 years. In a recent study, De Mascarel and colleagues28
examined co-occurrence and subsequent incidence of carcinoma associated with various types of atypia, and although CCA (which they referred to as FEA) had a 17% risk of concomitant invasive cancer, none of the 84 patients with FEA as an isolated diagnosis experienced malignant recurrence after 10 years of follow-up. Most recently, Martel and colleagues recognized 63 cases of FEA (flat DIN1) out of 1,751 core biopsies, with invasive carcinoma present in 7 ipsilateral follow-up excisions performed between 2 and 9 years following the initial procedure.30
Their conclusion amounted to a mild increase in cancer risk following a diagnosis of FEA on needle core biopsy.
As noted above, it is becoming increasingly clear that large numbers of atypical columnar cell lesions for assessment of long-term outcome are difficult to obtain, even with studies including several thousand initial breast biopsies. Since the overall risk for columnar cell lesions has, to our knowledge, never been established, we elected to assess this particular variable retrospectively in a large cohort of patients. We then proceeded to compare the risk associated with different subtypes of columnar cell lesions, based on Schnitt and Vincent-Salomon’s proposed classification scheme,2
in a nested case-control design.
Our findings have proven consistent with the results obtained from most of the aforementioned clinical outcome studies. In women who do not have atypical hyperplasia, the relative risk associated with the totality of columnar cell lesions with an average of 17 years of follow-up is 1.47 as compared to cases with neither proliferative breast disease nor columnar cell lesions (P=0.05). This represents only a mildly increased risk of subsequent cancer, and is comparable to what has been previously reported for EHLA.32, 39–41
This relative risk does not vary appreciably with time since biopsy. When comparing the different classes of columnar cell lesions with respect to future cancer risk, no significant difference was noted between CCL with and without atypia or hyperplasia.
Simultaneously, the prevalence of atypical hyperplasia appears to be increased 2–3 fold when columnar cell lesions are present as compared to when they’re absent (5.0% versus 1.9 % for ALH, 3.5% versus 1.4% for ADH). These findings are consistent with the previous observational studies, but seem to be true for all columnar cell lesions, not only ones with atypia, as suggested by previous studies that evaluated such atypical lesions exclusively.14, 15, 17
The remarkably strong association that both Abdel-Fatah and Leibl have shown between CCA and lobular neoplasia would normally suggest that the cancer risk associated with each of these entities should be comparable, a supposition that has so far largely failed substantiation. This might be explained by the postulate that lobular neoplasia (and probably atypical ductal hyperplasia as well) and atypical columnar cell lesions follow a path of co-occurrence rather than one of biologic progression. The plausibility of this postulate is increased by the fact that 16q deletions (where the E-cadherin gene is located) are common to both.3
When columnar cell lesions are present in isolation, their likelihood of progression to a more advanced lesion is minor. However, their mere presence is an excellent indicator for the presence of other atypical breast lesions that are associated with elevated cancer risk.
It is worth noting that, contrary to our expectation based on multiple previous studies, the cancer risk associated with EHLA is not significant, while the risk associated with CCL is what we would have expected from EHLA 40–43
. This might quite possibly be due to a confounding element introduced by the co-occurrence of CCL and EHLA, which was not accounted for in prior studies. Hence the mildly increased risk initially attributed to EHLA might be attributable to CCL coinciding with EHLA in the same benign biopsy.
The main limitations of this study are similar to those encountered by other studies tackling the clinical significance of columnar cell lesions and flat epithelial atypia. These include the overall small number of cases that harbor CCA, independently of more advanced atypical lesions. The limited availability of paraffin blocks on cohort cases contributes to this ever-recurring problem. The issue of diagnostic criteria, reproducibility, and interobserver variability, as illustrated by O’Malley et al.,6
is another potential limitation that was tentatively minimized through multistep review and consensus diagnosis of discrepant cases. Ideally, a similar large cohort of benign breast biopsies, where all CCL cases are subcategorized and assessed, would offer the best look at their clinical significance and implications towards future cancer risk as compared to the general population.
In summary, our results reinforce concepts that are being slowly rooted in our understanding of CCL of the breast. The presence of such lesions, whether they harbor or lack atypia, seems to have only mild implications towards increased future cancer risk. This assertion will still need continued substantiation by more studies with larger numbers and similar long-term follow-up. The more relevant implications, we believe, are those of association with potentially more worrisome lesions that necessitate further therapy. The appropriate corresponding management decisions will have to rely on targeted studies that would link mammographic findings, size of diagnostic biopsy, specific columnar cell lesion subtype, and extent of involvement. This is in order to insure that patients will not undergo unnecessary surgical excision for isolated lesions with questionable or minimal atypia. We do recommend however, whenever CCL is diagnosed, that a particularly careful search for AH be made.