Pathologic Upgrade Rates on Subsequent Excision When Lobular Carcinoma In Situ Is the Primary Diagnosis in the Needle Core Biopsy With Special Attention to the Radiographic Target

Patients with a diagnosis of LCIS in a needle core biopsy sample who subsequently underwent excisional biopsy of the same radiographically targeted area were identified from our surgical pathology files. Slides were reviewed and the diagnoses were confirmed in each case. An E-cadherin immunostain was available for review or was performed in all cases showing LCIS variants (florid or pleomorphic) and in cases in which the diagnosis of LCIS was not straightforward on hematoxylin-eosin examination.

Needle core biopsies containing a concurrent invasive carcinoma, ductal carcinoma in situ (DCIS), atypical ductal hyperplasia, a radial scar, or a papillary lesion were excluded. Cases with radiologic-pathologic discordance were also excluded because these cases would routinely be excised. Specifically, biopsies performed for a mass on imaging in which the histologic findings in the biopsy did not account for a mass lesion were excluded. At our institution, cases of LCIS found in a needle core biopsy have been routinely excised during the study period.

Specific microscopic features were recorded, including growth pattern and nuclear grade of LCIS, the number and percentage of cores containing LCIS, the presence of a coexisting columnar cell lesion, and the presence and location of calcifications in the biopsy.

The growth pattern of LCIS was classified as florid, nonflorid, or a combination of the 2 patterns. Florid LCIS is a distinct variant in which LCIS cells of low or intermediate nuclear grade exhibit direct (nonpagetoid) extension into ducts and cause marked expansion of ducts and lobules (Figure 1). This variant is frequently associated with necrosis and calcifications.^11–13  However, the term florid has also been used to describe only the architectural pattern seen in the florid variant of LCIS, and in this context, pleomorphic LCIS can be described as growing in this fashion.¹² 

Each case of LCIS was assigned a nuclear grade based on a 3-tiered system. Low nuclear grade LCIS cells are monomorphic, with small nuclei, scant cytoplasm, fine chromatin, and absent or indistinct nucleoli (Figure 2, A). These cells have been referred to as type A cells. Intermediate nuclear grade cells, referred to as type B cells, exhibit slight pleomorphism with larger nuclei, nucleoli, and more-abundant cytoplasm (Figure 2, B). Pleomorphic or high nuclear grade LCIS is characterized by cells with marked nuclear atypia, which can be seen in florid and/or nonflorid architectural patterns (Figure 2, C). In cases showing a combination of nuclear grades, a primary and secondary grade was recorded based on the prevalence of the grades in the sample.

To examine the extent of LCIS present in the biopsy sample, the number and percentage of cores containing LCIS were recorded. The number of cores present in each case was obtained from the pathology report's gross description. When the number of cores was not stated in the gross description, a microscopic count of the number of cores was performed.

The presence or absence of a coexisting columnar cell lesion in the needle core biopsy was recorded. Cases with flat epithelial atypia (atypical columnar cell change or atypical columnar cell hyperplasia) were excluded from the study because those cases are routinely excised.

The presence and location of calcifications were noted in each case. Specifically, we examined whether calcifications were present within the LCIS, in adjacent benign breast tissue, or in both components.

The imaging findings leading to core biopsy were obtained from radiology and pathology reports. The microscopic findings were correlated with the radiographic target in each case to determine whether LCIS was an incidental finding or the targeted abnormality. Lobular carcinoma in situ was considered an incidental microscopic finding in cases in which the targeted abnormality corresponded to a coexisting benign lesion in the biopsy. In cases targeted for calcifications, LCIS was determined to be incidental when calcifications were identified in breast tissue unassociated with LCIS. If calcifications were present exclusively within LCIS in a biopsy performed for calcifications, LCIS was considered the radiographic target.

Pathologic upgrade was defined as the presence of invasive carcinoma, DCIS, or pleomorphic LCIS (in cases in which only classic LCIS was present in the needle core biopsy) in the subsequent excisional biopsy specimen. Tests for statistical significance of the association between recorded parameters and pathologic upgrade were performed using the Fisher exact test.

Sixty-one needle core biopsies from 61 women ranging in age from 33 to 88 years (median, 54 years) were identified and included in this study. Five patients (8%) reported a family history of breast cancer, and one patient had a history of invasive carcinoma in the contralateral breast. Personal or family history of breast cancer was unknown in the remaining patients.

Of the 61 cases, the imaging finding leading to core biopsy was microcalcifications in 50 cases (82%), a mass/nodule in 7 cases (11.5%), abnormal magnetic resonance imaging enhancement in 3 (5%) cases, and an unspecified mammographic abnormality in 1 case (2%). Sampling was performed by 11-gauge or 9-gauge vacuum-assisted biopsy in 54 (88.5%) cases and by 18-gauge or 14-gauge automated core biopsy in 7 (11.5%) cases. The mean number of cores sampled per case was 9.5 (range, 2–36). The mean number of cores sampled was 9.8 cores per case for vacuum-assisted biopsy and was 7 cores per case for automated core biopsy; those differences were not statistically significant.

Overall, 6 of 61 cases (10%) of LCIS on needle core biopsy showed pathologic upgrade on excision (Table 1). Excisional biopsy diagnoses in upgraded cases included DCIS (2 of 6 cases; 33%), invasive lobular carcinoma (2 cases; 33%), invasive ductal carcinoma (1 case; 17%), and pleomorphic LCIS (1 case; 17%). Of the 6 cases with pathologic upgrade, the needle core biopsy was performed for mammographic microcalcifications in 5 cases (83%) and for a radiographically detected nodule in 1 case (17%), which corresponded to a fibroadenoma on biopsy.

Most cases of LCIS were of the classical type with low nuclear grade and nonflorid architecture (Table 2). Fifty-three of the 61 cases of LCIS (87%) showed nonflorid architecture, 5 cases (8%) showed a florid growth pattern, and 3 cases (5%) showed a combination of florid and nonflorid growth patterns in the biopsy. Cases with low nuclear grade and those with intermediate nuclear grade in a nonflorid pattern comprised 51% (31 of 62) and 36% (22 of 61) of the cases of LCIS on core biopsy, respectively. Cases with a combination of florid architecture and intermediate-grade nuclei (ie, florid variant of LCIS) included 6 of the 61 cases (10%), whereas 2 of the 61 cases (3%) showed pleomorphic LCIS, both of which grew in a florid growth pattern. Two of 8 cases (25%) showing florid LCIS on core biopsy were upgraded on follow-up excision. No cases of pleomorphic LCIS showed pathologic upgrade. Neither the architectural pattern nor the nuclear grade of LCIS on core biopsy was significantly associated with pathologic upgrade on excision.

Overall, the mean number of cores containing LCIS was 4.2 (range, 1–14 cores involved). The mean percentage of cores containing LCIS was 47% (range, 1/13 (8%) to 14/14 (100%). In cases showing pathologic upgrade on excision, the mean percentage of cores containing LCIS was 65% versus 45% in cases not upgraded (P = .04). Among upgraded cases, 50% showed at least 65% of cores containing LCIS and 20% showed 45% or less involved. Among all cases with fewer than 45% of cores containing LCIS, 3% showed pathologic upgrade. The number of cores containing LCIS was not significantly associated with pathologic upgrade. A coexisting columnar cell lesion was present on needle core biopsy in 36 of the 61 cases (59%). Four of the 36 cases (11%) with a coexisting columnar cell lesion were upgraded on excision, and the presence of a columnar cell lesion was not significantly associated with pathologic upgrade. Calcifications were present within the LCIS in 38 of the 61 cases (62%). Of the 38 cases containing calcifications within LCIS, 5 cases (13%) showed a pathologic upgrade on excision, which was not a statistically significant association.

Among cases targeted because of calcifications (n = 50), calcifications were present exclusively in LCIS in 10 cases (20%), and LCIS was considered the radiographic target in those cases. Lobular carcinoma in situ was also considered the radiographic target in one case biopsied for a mass in which the core biopsy showed florid variant of LCIS in 8 of 8 cores. The follow-up excision in that case showed florid LCIS without any other abnormality that would account for a mass on imaging. Pathologic upgrade occurred in 2 of the 11 cases (18%) in which LCIS was considered the targeted abnormality. Calcifications were present within both LCIS and adjacent benign breast tissue in 26 of the 50 cases (52%) targeted because of calcifications, 3 of which (11.5%) showed a pathologic upgrade on excision.

Lobular carcinoma in situ was considered to be an incidental microscopic finding in 24 cases. These cases included those in which the core biopsy was performed for calcifications and the calcifications were present in benign breast tissue adjacent to LCIS, but not within LCIS (14 of 50 cases targeted for calcifications; 28%). Nine of 10 cases (90%) cases found in biopsies targeted for a radiographic abnormality (mass, nodule, enhancement) in which LCIS was present in breast tissue adjacent to a lesion that was concordant with the radiographic target were also considered incidental. The 6 incidental cases targeted for a mass or nodule showed either a fibroadenoma or fibroadenomatoid change with stromal fibrosis on core biopsy. Three of 24 cases (12.5%) of incidental LCIS occurred in biopsies performed for an abnormal MRI enhancement. In 1 of these cases (33%), LCIS was present in a background of extensive columnar cell change and fibrocystic changes. In all 3 of the cases performed for an abnormal MRI enhancement, LCIS was present as rare foci of classical LCIS and was, therefore, considered incidental. Finally, in 1 of 24 (4%) incidental cases of LCIS, the biopsy was performed for an unspecific radiographic abnormality. In that case, LCIS was present amid extensive nodular sclerosing adenosis, which was considered the imaging abnormality, and LCIS was considered incidental in this case. Of the 24 cases where LCIS was considered an incidental microscopic finding on needle core biopsy, 1 case (4%) showed a pathologic upgrade on excision (Figure 3). In that case, the core biopsy was performed for a 1.1 cm nodule detected on screening imaging. The nodule corresponded to a fibroadenoma with sclerosing adenosis, that is, a complex fibroadenoma. Lobular carcinoma in situ was present in breast tissue outside of the fibroadenoma. Upon excision, a 0.25-cm focus of cribriform DCIS with intermediate nuclear grade was identified within the fibroadenoma. Lobular carcinoma in situ was also present within the fibroadenoma and in adjacent breast tissue.

There are numerous reports in the literature examining pathologic upgrade rates on follow-up excision when LCIS/ALH is found in needle core biopsy samples (Table 3). The rate of pathologic upgrade varies widely in the literature, and that variability can be explained by a number of factors. First, because of the uncommon occurrence of LCIS as a primary diagnosis in needle core biopsy samples, published studies have comprised relatively few cases and, therefore, are underpowered. Secondly, most of the studies are retrospective and have inherent selection biases because of varying management styles among clinicians as well as the presence of other risk factors that may have led to excision in some patients but not in others. Moreover, some studies include cases containing concurrent atypical duct hyperplasia, a diagnosis that would independently lead to excisional biopsy, thus contributing to further selection bias.^14–17  Furthermore, the inherent subjectivity in rendering a morphologic diagnosis of LCIS can represent an additional variable, and many studies have used the term lobular neoplasia to encompass LCIS and ALH lesions. Finally, radiologic-pathologic correlation, a routine exercise when evaluating pathologic findings in a needle core biopsy, has varied in published reports. Our study, specifically, is mainly limited by its retrospective nature.

A diagnosis of LCIS in a needle core biopsy showed an overall pathologic upgrade rate of 10% on subsequent excision in this study. We studied specific microscopic features in needle core biopsies known to be more commonly associated with either LCIS or concurrent malignancy. For instance, some studies have suggested that the extent of LCIS present in the needle core biopsy correlates with the rate of pathologic upgrade. In a series reported by Esserman et al,¹⁸  cases of lobular neoplasia were characterized as diffuse when greater than 1 lobule/core was involved by lobular neoplasia. Two of twenty-six cases (8%) were characterized as diffuse in their study, both of which were upgraded on excision. Rendi et al¹⁵  reported extensive involvement of lobular neoplasia on core biopsy to correlate with the risk of pathologic upgrade on excision. Extensive lobular neoplasia was defined as greater than 4 foci of lobular neoplasia on core biopsy, and 21% (6 of 29) of the cases with extensive lobular neoplasia were upgraded on excision, whereas 2.2% (1 of 46) of nonextensive cases were subsequently upgraded. In contrast, Karabakhtsian et al⁹  found that the number of terminal duct lobular units involved by LCIS/ALH had no effect on the rate of pathologic upgrade on follow-up excision. In an effort to determine whether the extent or volume of LCIS on biopsy correlated with pathologic upgrade, we recorded the number and percentage of cores involved by LCIS. The percentage of cores involved by LCIS, but not the number of cores, correlated with pathologic upgrade in our series. However, we believe that the number of cores involved by LCIS would likely be a better representation of the true extent of LCIS in the biopsy. Also, because of the wide variability in the number of cores taken, as well as the variably sized needle gauges used to sample lesions among studied cases, we believe the association of this parameter with pathologic upgrade may not be reproducible in other cohorts.

With the increased use of screening mammography and needle core biopsy sampling, columnar cell change has become a frequent finding in needle core biopsies performed for calcifications. The frequent association of columnar cell change with LCIS, invasive lobular carcinoma, and/or invasive tubular carcinoma has led to its recognition as a member of a family of low-grade neoplastic breast lesions.^19–24  Several studies^14,22,25  report the coexistence of columnar cell change with lobular neoplasia in needle core biopsy samples, with frequency rates ranging from 29% to 37%. However, no study has shown a correlation between the presence of a columnar cell lesion on core biopsy and pathologic upgrade. In our analysis, columnar cell change was present in association with LCIS on core biopsy in 59% (36 of 61) of the cases, but we found no significant correlation between the presence of a coexisting columnar cell lesion on core biopsy and pathologic upgrade on excision.

Lobular carcinoma in situ is classified as classic or pleomorphic, based on nuclear cytologic features. Although classic LCIS encompasses cases of LCIS with low and intermediate nuclear grades, pleomorphic LCIS is a high-grade lesion that exhibits marked nuclear atypia, mitotic figures, and is often associated with necrosis and calcifications. Reports of relatively few patients show high pathologic upgrade rates when pleomorphic LCIS is found on core biopsy.^7,26  Chivukula et al²⁶  reported that 3 of 12 cases (25%) of pleomorphic LCIS were upgraded to invasive lobular carcinoma on subsequent excision. A subsequent study by the same investigative group stressed the importance of distinguishing between low and intermediate nuclear grade LCIS as a greater pathologic upgrade rate was seen in cases showing intermediate nuclear grade.²⁷  In our study, which included 2 cases (3%) of pleomorphic LCIS that were not upgraded, we found no correlation between nuclear grade and pathologic upgrade rate.

Although LCIS has traditionally been divided into classic and pleomorphic types based on nuclear grade, the term florid has been used to describe an architectural feature, rather than a cytologic feature, of LCIS.¹²  On the other hand, the florid variant of LCIS, which has also been referred to as lobular intraepithelial neoplasia with comedo-type necrosis,²⁸  and lobular intraepithelial neoplasia 3, macroacinar variant¹¹  is a term reserved for examples showing marked ductal and lobular expansion by LCIS cells of low and intermediate nuclear grades. The presence of luminal calcifications allows the florid variant of LCIS to be easily detected on mammography and in some instances, including one case in our study, this subtype can form a localized mass.²⁸  The florid variant of LCIS has been reported to show a greater frequency of concurrent invasive carcinoma than has classic LCIS, and the invasive carcinoma is typically lobular.^4,12,29,30  In the current study, 2 of 8 cases (25%) of florid type LCIS found on core biopsy were upgraded on subsequent excision. In each of the 2 cases, invasive lobular carcinoma was found in association with florid type LCIS in the follow-up excisional biopsy. We believe the high pathologic upgrade rate on follow-up excision and frequent association with invasive carcinoma supports routine excision in patients with this variant of LCIS on needle core biopsy. However, larger studies are needed to validate our findings.

Historically, LCIS has been regarded as an incidental finding associated with lesions containing calcifications and has been thought to be undetectable on imaging studies. However, calcifications are commonly found within both classic and florid types of LCIS and are detectable radiographically.^23,25  The histogenesis of calcifications specifically associated with LCIS/ALH is unclear and one alternate possibility is that in some cases, LCIS/ALH secondarily involves ducts and lobules already populated by calcifications. The reported frequency of finding calcifications present within LCIS/ALH in needle core biopsy samples ranges from 8% to 41%.^{6,7,9,18,25,31,32}  In our series, we found calcifications to be present within LCIS in a significant percentage of cases (38 of 61; 62%), and that frequency was even higher among cases specifically targeting calcifications (36 of 50; 72%). Calcifications were present exclusively in LCIS in 10 of 61 cases (16%), and that finding was slightly more frequent among cases targeted for calcifications (10 of 50; 20%). However, despite the rather common colocalization of calcifications with LCIS, this finding did not correlate with the rate of pathologic upgrade in our study.

The common association of LCIS with calcifications in our study led us to question whether there was a difference in the pathologic upgrade rate based on whether the LCIS was the radiographically targeted lesion or a purely incidental finding. Although many studies discuss the importance of radiologic-pathologic correlation, very few have addressed whether LCIS is truly incidental or whether it represents the abnormality on imaging. Karabakhtsian et al⁹  reported that cases of LCIS/ALH with neoplastic epithelial calcifications, which were presumed to represent the radiographic target in their study, showed a higher rate of pathologic upgrade on follow-up excision. Nagi et al³¹  studied 45 patients with LCIS/ALH on core biopsy who underwent follow-up excision. All cases (100%) of LCIS/ALH in their study were determined to be incidental, and cases of type B LCIS and pleomorphic LCIS were excluded. Only 2 of 45 cases (4%) showed a pathologic upgrade on excision. Liberman et al⁴  found that of the 3 cases of incidental LCIS on needle core biopsy in their study, no (0%) DCIS or invasive carcinoma was found on excision. In contrast, a single reported study by Esserman et al¹⁸  documented that all cases (100%) of LCIS/ALH that were upgraded on excision (n = 3) were incidental in the core biopsy. In our study, we considered cases targeted for calcifications in which calcifications were present exclusively in LCIS to be the radiographic target. We also considered 1 case of extensive florid variant of LCIS in a biopsy performed for a mass lesion to be the radiographic target. When we correlated our microscopic findings with the radiographic targets, we found a trend toward a higher upgrade rate when LCIS represented the targeted abnormality versus when LCIS was present as an incidental finding (18% [2 of 11 cases] versus 4% [1 of 24 cases], respectively). Although our finding of a 4% pathologic upgrade rate was in line with that of findings by Nagi and colleagues,³¹  the difference from the pathologic upgrade rate when LCIS represented the targeted lesion was not statistically significant in our study.

Although there are no guidelines on whether follow-up excision is necessary in cases of LCIS diagnosed in a needle core biopsy, most authors support excision, particularly in certain circumstances. If there is radiologic-pathologic discordance on the needle core biopsy or if a residual mammographic abnormality is present after biopsy, follow-up excision should be performed. An excision should also be performed in cases in which LCIS shows morphologic features that overlap with those of DCIS, such as with cases of florid and pleomorphic variants of LCIS. Some would also support excision in high-risk patients, such as patients with a personal or strong family history of breast cancer. However, in cases in which classic LCIS is identified as an incidental finding in patients undergoing routine screening, particularly if LCIS is focal in the biopsy, an argument can be made for close clinical and radiologic follow-up because studies, including the current one, have shown low pathologic upgrade rates in these patients.^15–17,31 

In summary, finding LCIS as the most significant pathologic lesion in a needle core biopsy is uncommon. The optimal management of patients with LCIS/ALH on needle core biopsy continues to be debated. Although, for most patients, excisional biopsy is a prudent approach, it appears there may be a subset of patients where the most clinically significant lesion in the needle core biopsy is also an incidental finding and as such, can possibly be managed in a more-conservative, nonsurgical fashion. Additional studies are needed to verify this conclusion, but in the interim, we believe the proper management of these patients is best approached in a multidisciplinary setting.