This study aimed to ascertain pathologic findings of surgical follow-up excision (FUE) on patients who had radiologic finding of calcifications and lobular neoplasia (LN) on core biopsy. Breast core biopsy specimens from 2006–2011 with a diagnosis of pure classic-type LN (lobular carcinoma in situ [LCIS] and atypical lobular hyperplasia [ALH]) with no history of invasive carcinoma (IC) or ductal carcinoma in situ (DCIS) were studied. Two hundred thirty-seven patients with the diagnosis of calcium on radiologic studies had FUE and were included in the study. Cases were divided into group 1 (pure ALH, n = 163) and group 2 (pure LCIS, n = 74). The interval between the core biopsy and FUE ranged from 0.2 to 7 months (mean, 1.5 ± 1.1 months). The risk of upstaging on FUE (DCIS or IC) is as follows: LCIS, 8.1% (6/74) and ALH, 3.1% (5/163). The data indicate that there is a low risk of upstaging to DCIS/IC from a core biopsy diagnosis of lobular neoplasia.
Lobular carcinoma in situ, Atypical lobular hyperplasia, Breast core biopsy, Calcifications, Upstaging
Upon completion of this activity you will be able to:
define the upstaging rate on surgical follow-up excision (FUE) of patients who had a radiologic finding of calcifications and lobular neoplasia on core biopsy.
correlate upstaging on FUE in relation to atypical lobular hyperplasia or lobular carcinoma in situ.
discuss the relative risk and types of carcinoma in upstaging to invasive carcinoma from a core biopsy diagnosis of lobular neoplasia.
The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit ™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module.
The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.
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Lobular neoplasia (LN) both in the form of atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) is regarded as a definitive risk indicator for the development of invasive ductal or lobular carcinoma in both breasts. This association was first reported by Foote and Stewart1 in 1941, by demonstrating the coexistence of LCIS and invasive lobular carcinoma in 60% of their cases. Compared with the general population, the risk of breast cancer development is elevated up to 5-fold after a diagnosis of ALH and up to 10-fold after a diagnosis of LCIS.2–6 The term lobular neoplasia was introduced by Haagensen et al7 to discriminate it from ductal neoplasia, and they recommended a conservative approach in dealing with these lesions.
Currently, there are no well-established guidelines for the treatment of patients who receive a diagnosis of LN based on core-needle biopsy (CNB). Instead, the significance of these lesions on core biopsy is controversial, with relatively small samples described in existing literature. The most common treatment options are careful observation along with mammographic and clinical follow-up, and more recently, endocrine chemoprophylaxis for high-risk patients. The usefulness of surgical follow-up excision (FUE) is still debatable.8–14
Lobular neoplasia is typically asymptomatic and often lacks discriminating mammographic findings.15 Several imaging studies have found an association between microcalcifications and LN in significant numbers of cases.16–18 In addition to microcalcifications, LN may display radiographic findings of masses or architectural distortion.19,20
The goals of our study are to review a relatively large number of cases diagnosed as pure LN, without invasive carcinoma (IC), ductal carcinoma in situ (DCIS), or atypical ductal hyperplasia (ADH) on CNB that were followed by subsequent surgical excision, and correlate these cases with radiologic findings and surgical excision diagnoses. This is to further develop management guidelines for LN diagnosed on CNB.
Materials and Methods
This study was approved by the University of Pittsburgh School of Medicine institutional review board. A pathology database search at Magee-Women’s Hospital of the University of Pittsburgh Medical Center (UPMC) was performed for a study period of 66 months (January 2006 to July 2011). The biopsy specimens were received in separate formalin containers labeled “with calcification” and “without calcification” in most cases. Tissue cores were embedded in paraffin, sectioned, and leveled, and 5 slides were stained with H&E. Surgical excision specimens were fixed in 10% formalin, submitted entirely, and stained with H&E.
ALH was defined by uniform small cells filling and distending fewer than 50% of the terminal duct units of a lobule. The cells were discohesive and evenly spaced, with round nuclei and minimal pleomorphism. LCIS was diagnosed when the entire lobule was involved and more than 50% of the acini in the terminal duct units were distended.21 In this article, we use the term lobular neoplasia to include ALH and LCIS. Pathologic findings were divided into 2 groups: group 1 (pure ALH) and group 2 (pure LCIS with or without ALH).
A total of 807 cases of LN were identified out of 20,260 breast core biopsies (4%). Of these, 243 (30.1%) cases were excluded because of history or synchronous IC or DCIS, 96 (11.9%) because of radiologic diagnosis of mass or lesion other than calcifications, 123 (15.2%) because of the presence of ADH or flat epithelial atypia (FEA), and 7 (0.9%) because of the presence of pleomorphic component of LCIS. Those cases were excluded because the surgeon intended to excise the lesions. Among the remaining 338 cases of classic type LN, 237 (70.1%) had FUE. All cases had a screening mammogram with calcifications. The breast core biopsies were stereotactic, ultrasound, or magnetic resonance imaging–guided in 233 (98.3%), 3 (1.3%), and 1 (0.4%), respectively Table 1.
Patients’ clinical information, history, biopsy, and excisional results were extracted from the pathology reports. The slides of both CNB and FUE for the cases upstaged to DCIS or IC were reviewed by 2 authors (C.Z. and M.M.D.).
At our institution, stereotactic and magnetic resonance imaging–guided biopsies are usually performed with 9-gauge vacuum-assisted needles with a 12-mm-long trough; ultrasound-guided biopsies are usually performed with 14-gauge non–vacuum-assisted needles. The radiographic Breast Imaging Reporting and Data System (BI-RADS)22 scores (from 1–6) were recorded from the imaging data files. Cases were considered to be upstaged if FUE showed IC or DCIS.
Data were entered and analyzed using SPSS 16 (SPSS for Windows, SPSS, Chicago, IL); for qualitative data, frequency and percentages were used, and for quantitative data, range, median, mean, and standard deviation were used. χ2, Fisher exact, and independent t test were used to test significance between groups, and the cutoff point to detect significance (P value) was less than or equal to .05.
Table 1 illustrates the clinicopathologic and radiologic characteristics of LN cases with FUE biopsy that were included in the study. The mean and median ages of patients were 54 and 52 years, respectively (range, 28–79 years). The radiologic abnormalities reported for all cases and confirmed on biopsy showed calcium present mainly in fibrocystic changes, columnar cell changes, and benign breast ducts and stroma in most cases.
Upstaging of cases was not statistically significant between the 2 groups, with a higher frequency seen in the LCIS than in the ALH group (P = .102). No cases from the pure ALH cases were upstaged to ILC. Two cases of LCIS were upstaged to invasive lobular carcinoma (ILC) (2.7%). One (0.6%) of 163 ALH cases and 1 (1.4%) of 74 LCIS cases were upstaged to invasive ductal carcinoma, and 4 (2.5%) of 163 ALH cases and 3 (4.1%) of 74 LCIS cases were upstaged to DCIS. Collectively, 5 (3.1%) of 163 pure ALH cases and 6 (8.1%) of 74 pure LCIS cases were upstaged to DCIS with or without IC Table 2.
Clinicopathologic and Radiologic Characteristics of Lobular Neoplasia Cases Included in the Study (n = 237)
Cases upstaged to invasive carcinomas were (1) multifocal ILC, nuclear grade 2, largest focus measuring 1.3 cm, no lymphovascular invasion (LVSI), with associated calcification in benign ducts and biopsy site changes; (2) small focus of ILC, 0.12 cm, Nottingham grade 1, no LVSI, and biopsy site changes Image 1A and Image 1B; (3) focus of tubular carcinoma, 0.3 cm, Nottingham grade 1, no LVSI, with associated calcification in benign ducts and biopsy site changes; (4) tubular carcinoma, 2 cm, Nottingham grade 1, no LVSI, with associated calcification in benign ducts and biopsy site changes Image 1C, Image 1D, and Table 3.
Upstaging of Lobular Neoplasia on Surgical FUE
The DCIS phenotypes were cribriform (5 cases) Image 1E and Image 1F or solid (2 cases), and nuclear grades were grade 1 (4 cases), grade 2 (2 cases), and grade 3 (1 case). Comedonecrosis was focally present in the 2 cases (Table 3).
In cases upstaged to IC or DCIS specifically, specimens were obtained by 9-gauge Suros vacuum-assisted device (Suros Surgical Systems, Indianapolis, IN) (7 cases), 11-gauge vacuum-assisted core biopsy device (2 cases), 9-gauge Kopans needle (1 case) or 14-gauge biopsy device (1 case). The calcifications detected on mammography varied in description between clusters of pleomorphic to fine calcifications, some of which appear linear and uniform in shape with appearance of benign milk-of-calcium, and all calcifications were indeterminate (Table 3).
Interestingly, high-risk lesions, eg, ADH with or without FEA and FEA in the absence of ADH were identified in FUE in 33 (20.2%) of 163 cases of pure ALH and 21 (28.4%) of 74 cases of pure LCIS with core biopsy diagnoses Table 4.
No statistically significant difference was found in the BI-RADS score reported on core biopsy with upstaging of cases on FUE (P = .9). This may be because most cases were rendered a BI-RADS score of 4. The BI-RADS score was 4 in 230 (99.1%) of 232 cases, with no significant difference between the 2 groups or in relation to upstaging. The interval between the core biopsy and FUE ranges from 0.2 to 7 months (mean ± SD, 1.5 ± 1.1) (Table 1).
The mean age of the 11 patients upstaged to DCIS or IC was 56.8 years (8 [72.7%] of 11 patients >50 years) compared with 53.8 years in all other cases (n = 226) not upstage to DCIS or IC (156 [69.0%] of 226 patients ≥50 years).
Figure 1 is a summary flow chart with the number and percentage of cases upstaged to DCIS with or without IC in relation to clinicopathologic and radiologic findings.
ALH and LCIS are often multifocal and not uncommonly present in the contralateral breast. They have generally been considered to be risk factors for the development of bilateral breast carcinoma, with relative risk rates for ALH being 4 to 5 times and for LCIS up to 8 to 10 times those reported in the literature.18 This is in contrast to ADH and DCIS, which are considered by most as direct precursors to the development of malignancies.23
Management of isolated lobular neoplasia found on core biopsy is a controversial topic. Many studies have examined the need for excision biopsy for LN diagnosed on breast core biopsy. The data in the literature reflect mixed recommendations, divided between reexcision6,12,16–18,24 or not.8,23,25,26 Cancer at surgical excision ranged from 0 to 60%, which reflects the differences in the cases selected in addition to other factors. Pacelli et al27 reported no upstaging in 14 cases diagnosed with ALH and LCIS. Similarly, Renshaw et al28 reported no upstaging to carcinoma among 15 cases of LCIS and ALH. Jacobs et al29 reported no upstaging in 8 cases of ALH. Berg30 reported no upstaging in LCIS (0/8) cases and 14% upstaging in ALH (1/7) cases.
Comparable to our findings, Yeh et al31 reported 7% (1/15) upstaging in cases of unspecified LN.31 Shin and Rosen32 reported no upstaging in (0/5) cases of ALH on core biopsy. Similarly, Zhang et al33 and Liberman et al34 reported no upstaging of ALH cases (0/8 and 0/4, respectively). The highest rates of upstaging of LCIS to carcinoma were reported to be 60%,35 40% to 45%,36 30% to 37%,18,33,37 20% to 25%,32,34,38,39 and a meta-analysis showing 32% (77/241).40 Upstaging of ALH was reported to be as high as 43%,41 20% to 25%,18,37,39,42 14%,30,43 and 12.5%,35 with a meta-analysis showing 19% (53/280).40 The highest rates of upstaging of unspecified LN to carcinoma were reported to be 61%,44,45 35% to 46%,16,24,46,47 20% to 33%,20,48 15% to 14%,35,49–51 and 7%,31 with a meta-analysis showing 29% (72/246).
In this issue of ONCOLOGY, Drs Oppong and King provide an organized and comprehensive summary of guidelines for the clinical management of patients with lobular carcinoma in situ (LCIS). Although these approaches address breast cancer risk, it is noteworthy that management strategies for LCIS have not evolved from any unifying concept of LCIS as a disease—nor can they be targeted, as we are not able to predict with any certainty the disease course and outcome for individual women who carry the diagnosis. Rather, the authors present a set of interventions—logical though they are—that have necessarily been formulated piecemeal from diverse, fragmentary clinical and pathological observations. We should bear in mind that even the diagnosis of lobular neoplasia (LN; ie, LCIS and/or atypical lobular hyperplasia [ALH]) is accidental; it is usually an incidental finding on breast biopsies that were performed to target other lesions. LN has no distinctive clinical presentation or imaging features. The prevalence of LN therefore likely exceeds incidence. Thus, it might fairly be said that the clinical management of LCIS modifies an outcome that is driven at least as much by what we don’t see as by what we do see.
This awkward state of affairs is hardly surprising given the complexities of this disease process. Although we now know that all forms of LN are unified by functionally significant loss of E-cadherin gene expression, the histological distinction between ALH and LCIS is often problematic and based largely on subtle differences in the degree to which lobules are involved. Second, as demonstrated by the observed intervals between lobular neoplasia diagnosis and subsequent breast cancers, we know that the natural history of disease progression is quite variable but may be decades long, depending at least in part on whether there is occult malignancy present in unsampled breast tissue at the time of LN diagnosis. Finally, we know that lobular neoplasia is characterized not only by cytological heterogeneity but also by variable yet frequent multicentricity; however, we have no standard methods for quantifying either cytological type or volume of disease. The latter is relevant to the degree that cohort studies reveal strong associations between disease extent and patient risk.[1,2]
Most troubling from a pathogenetic standpoint is the apparently chimeric nature of LN as both a marker of constitutional (ie, bilateral) risk as well as a direct precursor for some invasive carcinomas. In our experience with ALH, the role of risk marker appears to be more prevalent. Specifically, we studied 175 women with ALH and followed them for later breast cancers. Breast cancer developed later in 34, and only 3 of these cancers were invasive lobular cancers. On the other hand, Page et al have reported the disproportionate ipsilateral cancer risk in patients with LN. Recent molecular studies, noted by King, have documented the role of direct precursor in some cases; these studies highlight the need for improved subclassification of LN in order to facilitate the individualization of local as well as systemic interventions. Collectively, the above considerations imply that definitive characterization of LCIS as a clinicopathological entity would be a daunting task and would likely require hundreds of patients, decades of follow-up, exhaustive tissue sampling, and comprehensive genomic analyses. We applaud Oppong and King for their recommendation of prospective studies, particularly with respect to surgical excision following core biopsy diagnosis and the assessment of margin status in these samples, since both these areas are of immediate clinical import and are lacking in sufficient data.
Is it possible, given the complexities reviewed above, to even propose a coherent explanation for the role of LN in breast carcinogenesis? We believe it would be useful to try, if only to provide a framework for the eventual testing of hypotheses. The following is an attempt to develop a preliminary basis for understanding:
1. LCIS is characterized by clonal genetic alterations and is therefore a neoplasm in the conventional sense of the term. However, while LN is a clue that other more aggressive lesions may be present in unsampled tissue, it may in some cases represent a self-limited process that lacks the cellular-genetic events necessary for neoplastic progression.
2. LN is a component and early manifestation of a definable subset of breast neoplasia having a distinctive gene expression signature and characterized by as yet undefined dysregulation of hormone receptors. In terms of genetic pathogenesis, recent studies demonstrate that LN and atypical ductal hyperplasia (ADH) have a greater degree of similarity than do ADH and high-grade ductal carcinoma in situ (DCIS).[4,5] Hence, the traditional distinction between “ductal” and “lobular” may have less relevance than that between low- and high-grade early precursor lesions. Although mortality data are limited, the few studies published do not suggest that LN constitutes a short-term risk for breast cancer death.
3. Unfortunately, to our knowledge there is presently no reliable clinical test to predict cancer risk for individual women with ALH or LCIS.[7,8] We believe that multiparameter models using number of foci, age, and other histological data may eventually refine our ability to predict subsequent breast cancer events. Eventual discovery of cellular or genetic changes might also better define progression potential. The well-documented outcome differences between pathologic LN subsets (ie, minimal ALH, ALH with ductal involvement, LCIS, etc) suggest that such advances are within reach.
Obviously the microscopic nature of LCIS, in addition to its complete lack of clinical detectability, represents a formidable barrier to the full elucidation of its role in breast cancer pathogenesis. Fortunately, the results of chemoprevention studies demonstrate that effective management is nonetheless possible without a detailed understanding of LCIS biology and pathogenesis. For those of us who study early events in breast cancer pathogenesis, clinical progress in the management of women with LN should emphasize not merely better prediction of which patients will develop breast cancers, but also improved ability to detect clinically occult markers of increased risk, including but by no means restricted to LN.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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