The goals of the current study were to compare the clinicopathologic presentations of patients with lobular carcinoma in situ (LCIS) as a component of breast carcinoma who were treated with breast conserving surgery (BCS) and radiation therapy (RT) with those of patients without LCIS as part of their primary tumor and to report rates of local control by overall cohort and specifically in patients with positive margins for LCIS and multifocal LCIS.

METHODS
Sixty-four patients with Stages 0-II breast carcinoma with LCIS (LCIS-containing tumor group, LCTG) that had received BCS+RT treatment at the University of Michigan between 1989 and 2003 were identified. These patients were matched to 121 patients without LCIS (control group) in a 1:2 ratio.

RESULTS
The median follow-up time was 3.9 years (range, 0.3-18.9 yrs). There were no significant differences between the two groups with regard to clinical, pathologic, or treatment-related variables or in mammographic presentation, with the exception of a higher proportion of the LCTG patients who received adjuvant hormonal therapy (P = 0.01). The rates of local control at 5 years were 100% in the LCTG group and 99.1% in the control group (P = 0.86). The presence of LCIS at the margins and the size and presence of multifocal LCIS did not alter the rate of local control.

CONCLUSIONS
The extent of LCIS and its presence at the margins did not reduce the excellent rates of local control after BCS+RT. The data suggest that LCIS in the tumor specimen, even when multifocal, should not affect selection of patients for BCS and whole-breast RT.

The Relation between the Presence and Extent of Lobular Carcinoma In Situ and the Risk of Local Recurrence for Patients with Infiltrating Carcinoma of the Breast Treated with Conservative Surgery and Radiation Therapy

Anthony L. Abner.   Cancer 88:1072-7, 2000

Between 1968 and 1986, 1625 patients with clinical Stage I-II invasive breast carcinoma were treated at the Joint Center for Radiation Therapy at Harvard Medical School with breast-conserving surgery (CS) and radiation therapy (RT) to a total dose to the primary site of 60 grays. Analysis was limited to 1181 patients with infiltrating ductal carcinoma, infiltrating lobular carcinoma, or infiltrating carcinoma with mixed ductal and lobular features who, on review of their histologic slides, had sufficient normal tissue adjacent to the tumor to evaluate for the presence of LCIS and also had a minimum potential follow-up time of 8 years.  One hundred thirty-seven patients (12%) had LCIS either within the tumor or in the macroscopically normal adjacent tissue. The 8-year crude risk of recurrence was not significantly increased for patients with LCIS associated with invasive ductal, invasive lobular, or mixed ductal and lobular carcinoma. Among the 119 patients with associated LCIS adjacent to the tumor, the 8-year rate of local recurrence was 13%, compared with 12% for the 1062 patients without associated LCIS. For the 70 patients with moderate or marked LCIS adjacent to the tumor, the 8-year rate of local recurrence was 13%. The extent of LCIS did not affect the risk of recurrence. The risks of contralateral disease and of distant failure were similarly not affected by the presence or extent of LCIS. Breast-conserving therapy involving limited surgery and radiation therapy is an appropriate method of treating patients with invasive breast carcinoma with or without associated LCIS. Neither the presence nor the extent of LCIS should influence management decisions regarding patients with invasive breast carcinoma.

Lobular carcinoma in situ. Pathology and treatment.

Gump FE.  Surg Clin North Am 1990 Aug;70(4):873-83

Lobular carcinoma in situ is a relatively "new" breast lesion, having been described only 50 years ago. It was originally thought to be a stage in the progression to invasive lobular cancer, but current evidence suggests that it is a marker of increased risk. It is certainly the most powerful of all risk factors, with studies suggesting that approximately 20 to 30 per cent of patients will go on to develop invasive cancer of various histologic types and with equal frequency in the biopsied and the opposite breast. There is general agreement concerning these facts, but considerable controversy remains about treatment. Haagensen and coworkers pioneered the concept of observation at a time when unilateral mastectomy was the standard treatment.

Lobular carcinoma in situ (LCIS): pathology and treatment.

Gump FE.  Cell Biochem Suppl 1993;17G:53-8

Lobular carcinoma in situ (LCIS) is not only a relative newcomer among breast lesions, but in its short span of 50 years it has gradually evolved from a rare form of breast cancer to being merely a marker of increased risk. Invasive cancer will develop in approximately 20-25% of women with LCIS provided there is sufficient follow-up after biopsy. Precise estimates are not possible since LCIS is an asymptomatic lesion that never makes a mass or reveals itself on mammography. It is found only by biopsy and thus the population being followed is a selected one. Every study has shown that when invasive cancer develops, it is just as likely to appear in the contralateral as in the biopsied breast, and invasive ductal cancers are more common than lobular. Clearly, the small round cells with pale cytoplasm that characterize LCIS do not go on to invasion in the usual patient; rather they serve to identify women who are more likely to develop breast cancer. Such patients represent a clearly defined group at increased risk, and for that reason are ideal candidates for chemoprevention. If tamoxifen or some other agent proves to be effective, the remaining arguments favoring mastectomy for LCIS will finally disappear.

Current treatment for lobular carcinoma in situ.

Gump FE, Ann Surg Oncol 1998 Jan-Feb;5(1):33-6
A questionnaire mailed to oncologic surgeons in 1988 revealed that 33% of the respondents still advised unilateral mastectomy, although a slim majority (54%) advised observation.   The identical questionnaire was mailed. Observation has yet to be universally accepted by the oncologic community, but at this time 85% of the respondents suggest it as the preferred option for their patients. Recent studies have questioned some of the tenets laid down by Haagensen in 1978, but it appears clear that his formulation of LCIS as a marker of increased risk continues to gain ground over the original concept of inevitable progression to invasive disease.

Alternatives in the surgical management of in situ breast cancer. A meta-analysis of outcome.

Bradley SJ. Am Surg 1990 Jul;56(7):428-32

The surgical management of lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS) remains controversial. For in situ breast cancer local excision (LE), local excision and radiation therapy (LERT) and mastectomy (MAST) have all been advocated.   As expected, recurrence rates following LE with both LCIS 8.4%) and DCIS (17%) are high. However, the overall mortality following mastectomy for recurrence, LCIS (2.8%) and DCIS (2.3%) does not differ statistically from those treated initially with mastectomy for LCIS (0.9%) and DCIS (1.7%).

Lobular carcinoma in situ: observation without surgery as an appropriate therapy.

Carson W/ Ann Surg Oncol 1994 Mar;1(2):141-6

The finding of lobular carcinoma in situ (LCIS) in the breast has generally prompted treatment with unilateral or bilateral mastectomy. Most experts now feel that LCIS simply identifies a woman who is at high risk to develop future breast cancer and requires only close clinical and mammographic follow-up. Four of 51 women treated with observation alone after diagnosis of LCIS developed breast cancer. All were detected by screening at an early stage. LCIS appeared to be an incidental finding on biopsy of mammographic abnormalities. The policy of observation alone for the finding of LCIS spares women mastectomy. Furthermore, cancers that develop in follow-up are likely to be detected at an early stage and be amenable to curative therapy. Observation alone is appropriate treatment for women with LCIS.

Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17. Five-year observations concerning lobular carcinoma in situ.

Fisher ER. Cancer 1996 Oct 1;78(7):1403-16

The cohort was comprised of 182 women with LCIS who were enrolled in National Surgical Adjuvant Breast Project (NSABP) Protocol B-17 but received no treatment other than lumpectomy. Nineteen pathologic features were assessed and related to ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor recurrence (CBTR) at a mean time on study of 5 years. RESULTS: Thirteen IBTR and 4 CBTR, including 1 instance of bilateral recurrence, were observed. All IBTR occurred in the same quadrant as the index LCIS. All 4 (2.2%) IBTR that were invasive cancers were of the lobular type, as was 1 of the 2 (1.1%) CBTR that were invasive. The other was a mucinous carcinoma. Three (1.6%) IBTR were pure ductal carcinoma in situ (DCIS) and another was accompanied by LCIS. These preliminary findings and historical information presented in this study fail to provide any reason to perform mastectomy on patients with LCIS.

The continuing dilemma of lobular carcinoma in situ.

Walt AJ. Arch Surg 1992 Aug;127(8):904-7; discussion 907-9

We reviewed the courses of 250 consecutive women with lobular carcinoma in situ of the breast entered into the Surveillance, Epidemiology, and End Results program of the Michigan Cancer  212 patients had mastectomy for the initial lesion and 65 patients had less than mastectomy, of whom one developed a new lesion in the ipsilateral breast. Thirty-seven patients (14.8%) were later found to have lesions in the contralateral breast, 25 within the first year. Thirteen of the 38 lesions (5.2% of the total series) were invasive, and 11 were primarily ductal. Seventeen patients died, two of breast cancer, two of unknown causes, and 13 of non-breast-related causes. The maximum mortality from breast cancer is 1.6% to this point. The frequency of mastectomy fell from 78.1% in the years 1973 through 1983 to 52% in 1984 through 1986

Lobular carcinoma in situ of the breast: results of a radiosurgical conservative treatment.

Cutuli B, Cedex, France. Oncol Rep 1998 Nov-Dec;5(6):1531-3

From 1980 to 1992, 17 women underwent lumpectomy (13) or quadrantectomy (4) and whole breast irradiation (median dose: 52 Gy) for pure lobular carcinoma in situ (LCIS). Three cases correspond to palpable lesions and 14 were discovered only by mammography. Twelve women also received tamoxifen at 20 mg/day for two years. With a median follow-up of 88 months, no local or regional recurrences have been recorded. The global rate of bilateral carcinoma was 17.6% (2 synchronous and one metachronous). In the literature, only eight other cases of LCIS were treated by lumpectomy and radiation therapy, but without details and data on long-term results. After biopsy alone for LCIS subsequent infiltrating carcinoma occurred in about 15% of the cases. Thus, the classical radiosurgical association should represent an interesting alternative both for biopsy alone and radical surgery until now only proposed to treat LCIS

Lobular carcinoma in situ as a component of breast cancer: the long-term outcome in patients treated with breast-conservation therapy.

Moran M, Yale University .Int J Radiat Oncol Biol Phys 1998 Jan 15;40(2):353-8

The purpose of this study is to assess the long-term outcome of breast cancer patients with a component of lobular carcinoma in situ (LCIS) treated with conservative surgery and radiation therapy.The pathology reports of all patients treated with conservative surgery and radiation therapy at our institution prior to 1992 were reviewed to identify patients who had LCIS as a histologic component. A total of 51 patients were identified. Primary histology of the 51 patients was as follows: 53% infiltrating lobular, 20% invasive and intraductal, 18% invasive ductal, 10% intraductal. Twenty-two patients (43%) in the LCIS group underwent reexcision. Of those, 69% had residual LCIS in the reexcision specimen. LCIS was characterized as focal in 29%, diffuse in 25%, and not specified in all other cases. The primary histology of the two populations differed significantly with a larger percentage of infiltrating lobular primaries in the LCIS group (53 vs. 5%). The LCIS group also differed from the control group with respect to the percentage of patients with bilateral disease (17 vs. 8%), and the percentage of patients with "false negative" mammograms (20 vs. 10%). There was no statistically significant difference between the LCIS group and control group in the 10-year overall survival (67 vs. 72%), distant disease-free survival (62 vs. 79%), or ipsilateral breast tumor recurrence-free survival (77% LCIS vs. 84% control). CONCLUSION: Patients with LCIS as a histologic component of breast cancer do not carry a worse prognosis than breast cancer patients without an LCIS component. Furthermore, the comparable local control rates between conservatively treated patients with or without LCIS suggests that patients with a histologic component of LCIS are suitable candidates for conservative surgery and radiation therapy.

Lobular carcinoma in situ increases the risk of local recurrence in selected patients with stages I and II breast carcinoma treated with conservative surgery and radiation
Aaron R. Sasson, Cancer 2001;91:1862

Lobular carcinoma in situ (LCIS) is a known risk factor for the development of invasive breast carcinoma. However, little is known regarding the impact of LCIS in association with an invasive carcinoma on the risk of an ipsilateral breast tumor recurrence (IBTR) in patients who are treated with conservative surgery (CS) and radiation therapy (RT). The purpose of this study was to examine the influence of LCIS on the local recurrence rate in patients with early stage breast carcinoma after breast-conserving therapy. Between 1979 and 1995, 1274 patients with Stage I or Stage II invasive breast carcinoma were treated with CS and RT. The median follow-up time was 6.3 years. LCIS was present in 65 of 1274 patients (5%) in the study population. LCIS was more likely to be associated with an invasive lobular carcinoma (30 of 59 patients; 51%) than with invasive ductal carcinoma (26 of 1125 patients; 2%). Ipsilateral breast tumor recurrence (IBTR) occurred in 57 of 1209 patients (5%) without LCIS compared with 10 of 65 patients (15%) with LCIS (P = 0.001). The 10-year cumulative incidence rate of IBTR was 6% in women without LCIS compared with 29% in women with LCIS (P = 0.0003). In both groups, the majority of recurrences were invasive. The 10-year cumulative incidence rate of IBTR in patients who received tamoxifen was 8% when LCIS was present compared with 6% when LCIS was absent (P = 0.46). Subsets of patients in which the presence of LCIS was associated with an increased risk of breast recurrence included tumor size < 2 cm (T1), age < 50 years, invasive ductal carcinoma, negative lymph node status, and the absence of any adjuvant systemic treatment (chemotherapy or hormonal therapy) (P < 0.001). LCIS margin status, invasive lobular carcinoma histology, T2 tumor size, and positive axillary lymph nodes were not associated with an increased risk of breast recurrence in these women.
CONCLUSIONS: The authors conclude that the presence of LCIS significantly increases the risk of an ipsilateral breast tumor recurrence in certain subsets of patients who are treated with breast-conserving therapy. The risk of local recurrence appears to be modified by the use of tamoxifen. Further studies are needed to address this issue.

Initially described as a form of breast carcinoma, LCIS is now considered a marker for an increased risk of breast carcinoma. With the increasing use of breast-conservation therapy for patients early stage invasive breast carcinoma, the impact of LCIS on breast recurrence rates has not been investigated thoroughly. The purpose of this study was to determine whether LCIS, when found in conjunction with an invasive tumor, has any effect on IBTR rates after patients undergo breast-conserving therapy.

Although the exact prevalence of LCIS in association with invasive breast carcinoma is unknown, the current series identified 65 incidents (5%) of LCIS in 1274 patients with early stage breast carcinoma. A centralized pathology review of the blocks and/or slides was not performed. However, all slides were reviewed by experienced pathologists at two National Cancer Institute-designated comprehensive cancer centers (i.e., the Fox Chase Cancer Center and the Hospital of the University of Pennsylvania) prior to the initiation of radiation therapy. It is possible that underreporting of the presence of LCIS may have resulted in the inclusion of some patients with LCIS in the non-LCIS group. However, the incidence of LCIS in our series is similar to that reported in other studies.Moran  identified 51 patients (4.6%) with LCIS among 1096 women with Stage I-II breast carcinoma who were treated with conservative surgery and radiation therapy. Abner reported a 12% incidence rate (137 patients) of LCIS in their series of 1181 women.

There are only a few published reports regarding the influence of LCIS on IBTR in patients who were treated with conservative surgery and radiation therapy. In the current series, patients with LCIS and Stage I or II breast carcinoma had 5-year and 10-year CI rates of IBTR of 5% and 29%, respectively. In contrast, patients without LCIS had 5-year and 10-year CI rates of 3% and 6%, respectively. This difference was statistically significant (P = 0.0003). Patients with LCIS had a higher rate of IBTR despite having more T1 tumors and more tumors detected solely by mammography. A recent study by Abner a concluded that the presence or extent of LCIS was not associated with an increased risk of IBTR. In their series, the 8-year crude rate of IBTR was 13% for 137 patients with LCIS compared with 12% for 1062 patients without LCIS. The crude rate of local recurrence in our series with a median follow-up of 6.3 years was 15% for patients with LCIS and 5% for those without. Therefore, although the rates of local recurrence in patients with LCIS in these two series appear similar, our 5% rate of breast recurrence in the non-LCIS patients was significantly lower than the 12% rate reported by Abner. Moran reported a 23% 10-year actuarial breast recurrence rate in 51 patients with LCIS who were treated with conservative surgery and radiation compared with a 17% rate in 1045 women without LCIS. These differences were not statistically significant. Only 54% of their patients underwent axillary dissection, 20% received tamoxifen, and 18% received chemotherapy. Fourteen percent of the LCIS patients had a positive margin for invasive carcinoma or DCIS. The status of resection margins in the non-LCIS patients was not stated. Therefore, in this series, a somewhat higher but not statistically significant risk of IBTR was observed in the LCIS patients, and, again, the rate of IBTR in the non-LCIS patients was higher than in our series. Griem  reported a 17% 5-year actuarial breast recurrence rate in 21 patients with LCIS treated with conservative surgery and radiation compared with 5% in patients without LCIS.

Our series is the first to evaluate prognostic factors for IBTR in patients with invasive carcinoma and LCIS compared with patients without LCIS. We found that an increased risk of IBTR was associated with the following factors: age 50 years, tumor size 2 cm, invasive ductal histology, negative axillary lymph nodes, and the lack of adjuvant systemic therapy. In contrast, IBTR was not increased in patients with typically unfavorable features, such as large tumor size (T2) or positive axillary lymph nodes. Although this observation may be explained in part by the more frequent use of adjuvant systemic therapy in these women, we noted a greater reduction in IBTR rates with the use of tamoxifen compared with chemotherapy. The 10-year CI rate of IBTR in women with LCIS was 41% for those who did not receive any adjuvant therapy compared with 29% for those who received chemotherapy and 8% for those who received tamoxifen. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial, tamoxifen resulted in a 56% reduction in the risk of invasive carcinoma in the 6% of patients in that study with LCIS alone. Our study suggests that tamoxifen also may reduce the risk of a subsequent invasive carcinoma in patients with LCIS that is found in association with invasive carcinoma.

LCIS has been shown to have a high rate of multicentricity and multifocality.  Therefore, the presence of LCIS at the surgical margins would not be unexpected. In our series, 14% of the LCIS patients had LCIS at the final margin. There were no IBTRs in these nine women compared with the 35% 10-year CI rate of IBTR in 56 women with negative margins for LCIS. The influence of LCIS at the surgical margins on IBTR rates was not evaluated in the series by Abner or Moran and Haffty. Fisher  suggested that negative margins of resection for LCIS in patients with LCIS only registered in the NSABP Protocol B17 trial may have accounted for the lower than expected risk of a subsequent invasive tumor. Further studies are needed to address this issue.

In our series, the majority of the breast recurrences were invasive and were located in the vicinity of the original primary tumor. However, the interval for IBTR was significantly longer in the LCIS patients (6.1 years vs. 4.8 years). For patients with LCIS and a true or marginal recurrence, the interval to recurrence was 6.9 years compared with 3.6 years for those without LCIS. True or marginal recurrences typically occur earlier than those in a separate quadrant and have been attributed to inadequate surgery or a significant residual tumor burden that was not controlled by moderate doses of radiation. The late pattern of these recurrences in the patients with LCIS may suggest the development of a new primary disease site. This pattern of the late development of malignancy also is seen in women with LCIS only where 50% of the subsequent tumors occurred more than 15 years after the original diagnosis of LCIS. In contrast, recurrences in a separate quadrant in patients with LCIS tended to occur earlier (3.7 years for patients with LCIS vs. 7.7 years for patients without LCIS). This observation may reflect an underestimate of the extent of the initial disease with significant residual disease beyond the area of the primary surgery. The site of the breast recurrence or the interval to its appearance in patients with invasive disease and LCIS has not been reported in other series.

Similar to the series reported by Abner we did not identify an increased risk of contralateral breast carcinoma in women with LCIS. Moran  reported bilateral breast carcinoma (synchronous or metachronous) in 16% of their 51 patients with LCIS and in 8% of their 1045 women without LCIS (P = 0.05). A positive family history of breast carcinoma in a first-degree relative in women with LCIS was associated with a 10-year CI rate of IBTR of 47% and a 10-year rate of contralateral breast carcinoma recurrence of 30% in this series. In other series of women with only LCIS, a positive family history of breast carcinoma has not been correlated with an increased risk of breast carcinoma. Tamoxifen decreased the risk of IBTR as well as contralateral breast carcinoma in women with or without LCIS in this series. However, the magnitude of the reduction was greater for women with LCIS.

In summary, in the current study, the presence of LCIS significantly increased the risk of IBTR in some, but not all, patients who were treated with breast-conserving therapy. These recurrences often were invasive, frequently were found in the index quadrant, and tended to appear later than those in women without LCIS. Women age 50 years appear to have an increased risk of local disease recurrence compared with older women. Furthermore, the risk of local disease recurrence appears to be decreased by the adjuvant use of tamoxifen. Further studies are needed to investigate this issue.