Although LCIS was first described by Foote and Stewart in 19411
, management of the patient with LCIS, both alone or in conjunction with invasive carcinoma, has remained controversial. Until relatively recently, LCIS was accepted as a risk factor for the development of invasive breast carcinoma in both the affected and non-affected breast.2, 3
Recently, several lines of evidence have suggested that LCIS may be a precursor of invasive carcinoma, resulting in the need to reevaluate its clinical management when it occurs in conjunction with invasive carcinoma or DCIS. Evidence suggesting that LCIS may be a precursor lesion includes the significantly greater risk of developing cancer in the ipsilateral breast after a diagnosis of LCIS reported in recent studies16, 17
, the high proportion of infiltrating lobular carcinomas that occur following a diagnosis of LCIS, usually seen in the same quadrant of the breast where LCIS was identified17
, the presence of shared molecular alterations in LCIS and co-existing ILC6, 18
, and the recognition of histologic variants of LCIS, such as pleomorphic LCIS with molecular profiles suggestive of a more aggressive biology.18
If LCIS is a precursor lesion, its presence in the lumpectomy specimen, particularly at the specimen margin, would be expected to be associated with an increased risk of local recurrence. In this study, which included 290 patients with LCIS, we found no evidence that the presence of LCIS at the margin or in the lumpectomy specimen increased the incidence of local failure after treatment with excision and radiotherapy. The presence of LCIS in the specimen, but not at the margin, is relevant to the question of the biology of LCIS as a precursor, since studies of mastectomy specimens have demonstrated that more than 50% of patients diagnosed with LCIS have multiple foci in the ipsilateral breast.3
If LCIS is a precursor lesion, patients with LCIS at the specimen margin would be anticipated to have a higher incidence of TR/MM recurrences, while those with LCIS in the specimen but not at a margin might be expected to have an increase in recurrences in other areas of the breast (i.e. “elsewhere” recurrences). No trend toward either of these outcomes was observed.
Other studies which have examined the impact of LCIS on local control after breast conserving therapy are summarized in .7–11
The majority of these studies have found no relationship between LCIS and local recurrence. Our study confirms these results in a large group of patients all known to have margins free of invasive carcinoma or DCIS. Prior studies, including an earlier report from the Fox Chase Cancer Center that found LCIS to be associated with an increased risk of local recurrence11
, have included patients with positive or unknown margin status.
Summary of other studies examining impact of LCIS on local control after breast-conserving therapy
Approximately 22% of patients in the initial Fox Chase Cancer Center study had positive or unknown margins, a finding known to be associated with LR, making interpretation of the positive results of the study difficult. Margins free of invasive or intraductal carcinoma were a requirement for entry into our study, and the proportion of patients with margins of 2 mm or less did not differ between groups. In addition, with the exception of the report of Ben-David et al.8
, which was a matched pair analysis, other studies that have examined this question have not taken into account the increased frequency of the diagnosis of LCIS in more recent time periods. This is important since rates of local recurrence have decreased steadily over time19, 20
, and differences in the dates of treatment of patients with and without LCIS have the potential to mask the effect of the lesion on local control. Local recurrence rates have decreased over time due to improved techniques in both surgery and RT, more detailed pathologic evaluation of margin status, and increased use of adjuvant therapies such as tamoxifen. The decline in LR in more recent time periods, coupled with the increased frequency of the diagnosis of LCIS in the same time period, has the potential to obscure the effect of LCIS on local control if not taken into account. The studies of Moran and Hafty10
and Abner et al.7
report considerably higher rates of local recurrence in the non-LCIS control groups than are observed today, and may not be relevant to current practice. In common with the study of Jolly et al.9
, we found that the presence of LCIS was associated with a higher incidence of infiltrating lobular carcinomas, a lower grade of invasive carcinomas, a higher likelihood of estrogen receptor positivity, and a greater use of tamoxifen. The 10-year local failure rate of 7% reported for their control group is very similar to the 6% reported in our study, but in contrast to the doubling of the risk of local recurrence that they observed in the LCIS group, we did not see a significant difference in LR. The reasons for this are not clear. One difference between our study and theirs is that we did not review the pathology slides, but based our classification of the presence or absence of LCIS on the initial diagnosis, while Jolly et al. conducted a review of the pathology specimens of both cases and controls. The number of cases initially classified as having LCIS who were found not to have LCIS on re-review is not stated, nor is the number of cases in the control group found to have LCIS. However, we believe that it is extremely unlikely that there are significant numbers of patients in our study whose LCIS status was misclassified. All of the pathology was read by a group of pathologists whose practice was limited to cancer, and all specimens from outside institutions were reviewed at the Fox Chase Cancer Center.
While our study and the bulk of the published literature provides reassurance that the presence of LCIS in association with invasive or in situ carcinoma should not be considered when assessing patient suitability for BCT or the need for re-excision, studies of pure LCIS indicate that the time to development of cancer after a diagnosis of LCIS may be extremely prolonged. In the study of Rosen et al. the average interval to the development of cancer was 20.4 years after biopsy3
, although in the study of Page et al. 75% of cancers developed within 15 years of biopsy.21
The median follow-up of our study was 5.2 years, so we cannot exclude the possibility that with a longer follow-up duration, an impact of LCIS on local recurrence might be observed. However, the time to LR in patients with LCIS (58 months) was significantly shorter than the time to LR in those without LCIS (71 months; p < 0.0001), making it unlikely that further follow-up would change the study outcome. In addition, other published studies have median follow-up periods ranging from 3.9 years to 13.4 years, and those with the longest follow-up periods do not demonstrate an association between LCIS and local recurrence. Our study included patients who were recognized as having LCIS prior to the advent of e-cadherin staining, and the conclusions cannot be extrapolated to patients with uncommon morphologic variants of LCIS, such as pleomorphic LCIS which may not have been classified as LCIS during the time period of our study. Further information on the natural history of these lesions is needed to determine their impact on surgical therapy.
In conclusion, our study did not find a statistically significant increase in LR in patients found to have LCIS co-existent with invasive carcinoma or DCIS treated with breast-conserving surgery and RT. Therefore, we believe that re-excision is not indicated if LCIS is present or close to margin surfaces. As long as final margins are negative for invasive carcinoma or DCIS, patients with LCIS should receive post-operative RT and adjuvant therapy in same manner as those without LCIS, and are appropriate candidates for breast conservation.