Lobular Carcinoma In Situ Variants in Breast Cores

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1 Lobular Carcinoma In Situ Variants in Breast Cores Potential for Misdiagnosis, Upgrade Rates at Surgical Excision, and Practical Implications Megan E. Sullivan, MD; Seema A. Khan, MD; Yurdanur Sullu, MD; Carol Schiller, MD; Barbara Susnik, MD, PhD N Context. Differentiating ductal carcinoma in situ (DCIS) from lobular carcinoma in situ (LCIS) on core biopsy has important clinical implications. Lobular carcinoma in situ variants, including LCIS with necrosis and pleomorphic LCIS, share morphologic features with solid DCIS that may lead to misclassification. Objectives. (1) To review all LCIS variants diagnosed in core biopsies at Northwestern University, Feinberg School of Medicine, and determine the frequency of misinterpretation of variant LCIS as solid DCIS in archival core biopsies, and (2) to determine the frequency of upgrade to invasive carcinoma or DCIS in the surgical excision. Design. Consecutive core biopsies with original diagnoses of predominantly solid DCIS without invasion that were performed between January 2001 and December 2005 at Northwestern University, Feinberg School of Medicine, were selected for E-cadherin staining. The revised diagnosis of LCIS was based on E-cadherin negativity and morphology. The frequency of LCIS variants A diagnosis of ductal carcinoma in situ (DCIS) versus lobular carcinoma in situ (LCIS) has important clinical implications for the patient because therapeutic priorities are different for each entity. Historically, LCIS is characterized microscopically by a population of discohesive, small, monotonous cells with intracytoplasmic lumina that fill and expand the lobule. 1 The distinction from DCIS was relatively clear. However, recently described variants of LCIS, including LCIS with necrosis (LCIS-N) and pleomorphic LCIS (LCIS-P), share some morphologic features with solid DCIS, thus rendering precise diagnosis difficult on routine hematoxylin-eosin stained sections in some core biopsies. 2,3 The E-cadherin Accepted for publication August 26, From the Departments of Pathology (Drs Sullivan, Sullu, Schiller, and Susnik) and Surgery (Dr Khan), Northwestern University, Feinberg School of Medicine, Chicago, Illinois. Dr Sullu is now with the Department of Pathology, Ondokuz Mayis University, Faculty of Medicine, Samsun, Turkey. The authors have no relevant financial interest in the products or companies described in this article. Presented in part at the annual meeting of the United States and Canadian Academy of Pathology, Boston, Massachusetts, March 10, Reprints: Megan E. Sullivan, MD, Departments of Pathology, Northwestern Memorial Hospital, Feinberg Pavilion, 7th Floor, 251 E Huron St, Chicago, IL ( megan-sullivan@northwestern. edu). upgraded was then estimated from all core biopsies with original or revised diagnoses of pleomorphic LCIS or LCIS with necrosis. Results. Among 75 cases of solid DCIS, 10 (13.3%) were reclassified as LCIS, including 9 variants (5 pleomorphic LCIS, 4 LCIS with necrosis) and 1 classic LCIS. Twenty-eight patients comprised the entire group of LCIS variant cases (both reclassified and originally diagnosed cases). Seven patients with LCIS variants (25%) were upgraded to invasive lobular carcinoma in surgical excision (4 of 11 cases of LCIS with necrosis [36%] versus 3 of 17 cases of pleomorphic LCIS [18%]). Conclusions. About one-tenth of solid DCIS diagnosed in core biopsies in the past may represent LCIS variants. These show a 25% upgrade to invasive lobular carcinoma in surgical excision. The distinction of an LCIS variant from DCIS is important because of its implications for radiation therapy, although it may not affect surgical management. (Arch Pathol Lab Med. 2010;134: ) immunohistochemical stain is increasingly being used to identify lobular neoplasia and has been shown to be helpful in classifying carcinomas in situ with indeterminate features as either ductal or lobular. 4 E-cadherin is a transmembrane protein that mediates cell-to-cell adhesion as well as several signal transduction pathways. Loss of membranous E- cadherin expression is characteristic of lobular neoplasia, whereas most ductal neoplastic proliferations, as well as benign breast epithelium, maintain expression. 5 7 In addition, E-cadherin reactivity in carcinoma in situ was shown to modulate the pathobiologic potential of these lesions as a subset of LCIS with focal membranous reactivity exhibited clinical behavior similar to DCIS. 8 When LCIS-P and LCIS-N were initially described as distinct clinicopathologic entities in the literature, E- cadherin immunohistochemistry was not routinely applied for cases with overlapping morphology, and some of these lesions were diagnosed as DCIS. Therefore, we decided to identify LCIS cases that were originally interpreted and treated as DCIS and establish their frequency relative to solid DCIS. Current understanding of ductal and lobular carcinoma in situ is based on studies that included lesions that were classified solely on morphologic criteria, 9,10 with LCIS consisting entirely of lesions meeting criteria for the classic form of LCIS. Although DCIS is a known precursor to invasive 1024 Arch Pathol Lab Med Vol 134, July 2010 LCIS Variants in Breast Cores Sullivan et al

2 and LCIS-N) is less understood, but there is growing evidence that these lesions have a significant association with invasive lobular carcinoma, suggesting their potential for direct progression into invasive carcinoma.2,3,12,13 Noting this association, we decided the second aim of this study should be to determine the frequency of upgrade to lesions that require more extensive treatment (ie, DCIS or invasive malignancy) when LCIS variants are diagnosed on core biopsy. MATERIALS AND METHODS Review of Archival Core Biopsies With Original Diagnosis of Solid DCIS Figure 1. A, E-cadherin negative lobular carcinoma in situ (LCIS) with adjacent unremarkable lobule showing diffuse membranous positivity. B, Pleomorphic LCIS. C, Lobular carcinoma in situ with necrosis (E-cadherin, original magnification 310 [A]; and hematoxylineosin, original magnifications 340 [B] and 310 [C]). Following Institutional Review Board approval, consecutive needle-core biopsies of the breast with an original diagnosis of DCIS with solid architecture (including both solid-type DCIS with and without necrosis and comedo-type DCIS) without an associated invasive carcinoma performed between January 2001 and January 2005 at Northwestern University, Feinberg School of Medicine, were retrieved from the pathology files. On review, examples of DCIS with significant micropapillary or cribriform architecture and cases with insufficient diagnostic tissue remaining for immunohistochemical staining were excluded, and the remaining specimens were stained by E-cadherin. Immunohistochemical staining was performed using a dextran polymer conjugate visualization system and a primary mouse anti-human E-cadherin antibody (clone NCH-38, 1:200 dilution; DAKO, Carpinteria, California). The E-cadherin immunostaining was interpreted as positive when there was diffuse, weak, moderate, or strong membranous staining of the carcinoma in situ cells. Staining was interpreted as negative when no membranous staining of the carcinoma in situ cells was present. Adjacent benign ducts and lobules showing strong complete membranous staining served as internal and external positive controls (Figure 1, A). The diagnosis of LCIS on review was based on E-cadherin negativity as well as morphologic criteria. A proliferation was classified as LCIS-C when composed of a uniform population of small, discohesive cells within a variably distended lobule that possessed round to oval, bland nuclei and intracytoplasmic vacuoles. Although other definitions exist, the threshold used in this study for the distinction of LCIS versus atypical lobular hyperplasia was involvement of at least 75% of the units of a lobule.1 The diagnosis of LCIS-P required a variably discohesive population of pleomorphic, medium to large cells, with nuclei at least 3 times the size of a small lymphocyte that were eccentrically placed with distinct nucleoli.2 Necrosis and microcalcifications were frequently present, but not obligatory, for the diagnosis of LCIS-P. In LCIS-N, cells with classic lobular cytology displayed luminal necrosis and often marked distension of ductules.1 The necrosis was defined as either (1) a punctate type, when a collection of nuclear fragments was present focally within the LCIS; or (2) a comedo type, when prominent plugs of necrotic material were present in the lumen of the glandular spaces distended by LCIS. Although morphologic overlap existed between the LCIS variants because of the presence of necrosis in most LCIS-P cases, we distinguished LCIS-P from LCIS-N by the presence of a cytologically pleomorphic LCIS cell population that represented at least 10% of the LCIS cells in the former. Information regarding the subsequent surgical excision findings was pulled from the pathology database in all cases stained for E-cadherin, and the slides were reviewed in selected cases, including all cases with a modified diagnosis on review. Upstaging of LCIS Variants Diagnosed in Core Biopsy carcinoma, classic LCIS (LCIS-C) is considered a marker of increased risk for development of invasive breast carcinoma rather than a direct precursor lesion.9,11 The natural history of the recently described variants of LCIS (LCIS-P Arch Pathol Lab Med Vol 134, July 2010 Following Institutional Review Board approval, consecutive needle core biopsies of the breast with an original diagnosis of either LCIS-P or LCIS-N (confirmed by negative E-cadherin immunohistochemistry) without associated invasive carcinoma LCIS Variants in Breast Cores Sullivan et al 1025

3 Figure 2. Screening mammogram from patient 18 (see Table 1), a 43-year-old woman with indeterminate calcifications (Breast Imaging-Reporting and Data System 4B) biopsied using a 9-gauge needle with vacuum assistance and stereotactic guidance showing florid lobular carcinoma in situ with necrosis. Figure 3. Patient 18 had a 0.5-cm invasive lobular carcinoma in her needle-localized surgical excision with negative margins and a negative sentinel lymph node biopsy (hematoxylin-eosin, original magnification 310). performed between January 2001 and January 2009 at Northwestern University, Feinberg School of Medicine, were retrieved from the pathology records. We reviewed the pathology of the core biopsy specimens and the subsequent pathology of the surgical excision of the core biopsy site. An upgrade was defined as the finding of a lesion in the surgical specimen (adjacent to the core biopsy site) such as invasive carcinoma or DCIS that would warrant additional treatment, such as complete excision and radiation therapy. Statistical differences were assessed using the x2 test or t test (P values,.05 were considered statistically significant). RESULTS Review of Archival Core Biopsies With Original Diagnosis of Solid DCIS On review of 135 consecutive needle core biopsies of the breast with an original diagnosis of solid DCIS without an associated invasive carcinoma, those with significant micropapillary or cribriform architecture, and those with insufficient diagnostic tissue remaining for immunohistochemical staining were excluded (n 5 56; 41%). The remaining 79 core biopsy specimens were stained with E-cadherin. Four additional cases were dropped because no lesional tissue remained on the deeper level used for E-cadherin immunohistochemistry, leaving 75 core biopsies included in the study. Membranous E-cadherin positivity was present in 86.7% of cases (65 of 75) and E-cadherin was negative in 13.3% of cases (10 of 75) originally diagnosed as solid DCIS. On review of the hematoxylin-eosin stained sections and immunohistochemistry results, all E-cadherin negative cases were reclassified as LCIS, including 1 LCIS-C and 9 variants (5 LCIS-P and 4 LCIS-N), (Figure 1, B and C). The original grade of reclassified cases was 1 (1 case; 10%), 2 (7 cases; 70%), and 3 (2 cases; 20%). Eight of the 10 total reclassified cases (80%) showed necrosis, including all LCIS-N (4 of 4; 100%) and 4 LCIS-P (4 of 5; 80%). Seven of the 9 cases reclassified as LCIS variants (78%) had surgical follow-up at our institution and were included in the upgrade analysis Arch Pathol Lab Med Vol 134, July 2010 LCIS Variants Diagnosed in Core Biopsy: Clinicopathologic Features and Frequency of Upgrade in Surgical Specimens We identified 28 patients with a LCIS variant diagnosed by core biopsy and with surgical follow-up available, including 7 cases (25%) with an original diagnosis of solid DCIS revised to an LCIS variant (Table 1). Only LCIS variants without an invasive component or accompanying DCIS in the core biopsy were included. The entire group (n 5 28) consisted of 11 LCIS-N (39%) and 17 LCISP (61%). Patient ages ranged from 41 to 70 years (mean, 54.5 years). The radiologic imaging target was a mass in 3 cases (11%) and calcifications in the remaining 25 cases (89%) (Figure 2). Lesions were sampled by core biopsy with stereotactic (n 5 24; 86%), sonographic (n 5 2; 7%), or magnetic resonance imaging (n 5 2; 7%) guidance. Ten patients had a family history of either a mother or sister with breast carcinoma (10 of 28; 36%). Eight patients (8 of 28; 29%) had a personal history of ipsilateral breast carcinoma, including 3 individuals (3 of 28; 11%) with previous carcinoma and 5 patients (5 of 28; 18%) with synchronous carcinoma in another quadrant (Table 1). These ipsilateral cancers included DCIS (n 5 3) and invasive ductal (n 5 2), mammary (n 5 2) and lobular (n 5 1) carcinoma. Two patients had contralateral, but synchronous, invasive carcinoma of the ductal type (2 of 28; 7%). Overall, LCIS variants were upgraded to invasive carcinoma in 25% (7 of 28) of excisional specimens (Table 2). A comparable upgrade rate was seen in the Ecadherin positive DCIS core biopsies from our study set with available surgical excision pathology (16 of 60; 26.7%). All of the invasive cancers associated with LCIS variants were lobular type (Figure 3). There was a trend toward younger patients in the upgrade to invasive lobular carcinoma (mean, 49.7 years) as opposed to patients without an upgrade (mean, 56.1 years); however, that finding was not statistically significant (t test, P 5.09). The size of upgraded invasive lobular carcinomas in surgical specimen ranged from less than 0.1 to 1.5 cm LCIS Variants in Breast Cores Sullivan et al

4 Table 1. Case No. Age, y Characteristics of Patients With Lobular Carcinoma In Situ (LCIS) Variant Diagnosed by Core Biopsy and With Surgical Follow-up Available a,b Radiologic Findings History of Ipsilateral Cancer Original dx, Grade Reviewed dx Surgery Upgrade on Excision Radiation Therapy 1 69 Calcifications Synchronous IDC and ILC solid DCIS 3 LCIS-P M No No 2 57 Calcifications None solid DCIS 2 LCIS-N L, M ILC Yes 3 48 Calcifications Previous IMC (8 mo) solid DCIS 2 LCIS-P L No Yes (for IMC) 4 42 Calcifications None solid DCIS 3 LCIS-P L ILC Yes 5 53 Calcifications None solid DCIS 2 LCIS-N M ILC No 6* 70 Calcifications None solid DCIS 2 LCIS-N L No Yes 7 54 Calcifications Previous IMC (3 y) solid DCIS 2 LCIS-N M No No 8 61 Calcifications Synchronous IDC, DCIS LCIS-N LCIS-N M No No 9 59 Calcifications None LCIS-N LCIS-N L ILC Yes 10* 41 Calcifications None LCIS-P LCIS-P L No No Calcifications Synchronous DCIS LCIS-N LCIS-N L x2 DCIS Yes 12* 58 Mass None LCIS-P LCIS-P L No Yes 13* 45 Calcifications None LCIS-P LCIS-P L No No Calcifications Previous DCIS (6 y) LCIS-P LCIS-P L No No 15* 62 Calcifications None LCIS-P LCIS-P L No No 16* 46 Calcifications None LCIS-N LCIS-N L No Yes Calcifications None LCIS-P LCIS-P L ILC Yes Calcifications None LCIS-N LCIS-N L ILC Yes 19* 58 Calcifications None LCIS-P LCIS-P L No No Calcifications None LCIS-P LCIS-P L ILC Yes Calcifications None LCIS-P LCIS-P L DCIS Yes 22* 52 Calcifications None LCIS-P LCIS-P L No No 23* 52 Calcifications None LCIS-P LCIS-P L No No Mass None LCIS-P LCIS-P M No No 25* 64 Calcifications None LCIS-N LCIS-N L No No Calcifications Synchronous ILC LCIS-P LCIS-P M No No Calcifications Synchronous DCIS LCIS-N LCIS-N L No Yes Mass None LCIS-P LCIS-P M DCIS No Abbreviations: DCIS, ductal carcinoma in situ; dx, diagnosis; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; IMC, invasive mammary carcinoma; L, lumpectomy; LCIS-N, lobular carcinoma in situ with necrosis; LCIS-P, pleomorphic lobular carcinoma in situ; M, mastectomy. a Only cases with surgical follow-up are included in the table. b Cases with an asterisk (*) represent pure LCIS (patients with no personal history of invasive carcinoma and no upgrade in their excision). (mean, 0.4 cm). The upgraded invasive lobular carcinomas were staged as T1mic (n 5 4; 57%), T1a (n 5 2; 29%), and T1c (n 5 1; 14%). Two patients with large synchronous ipsilateral invasive carcinomas in other quadrants had positive lymph nodes. None of the 3 lesions presenting as a radiologic mass was upgraded and 6 of 25 lesions (24%) presenting with calcifications were upgraded. Even the largest upgraded invasive carcinoma (size, 1.5 cm) presented only with calcifications on the original mammogram. The calcifications were associated with the LCIS variant in 6 of the 7 upgrades (86%), and in all cases, the calcifications were present in luminal necrotic material. In the remaining patient with an upgrade at excision, the calcifications were present only in adjacent breast tissue. Upgrade to invasive carcinoma was more frequent in LCIS-N (4 of 11; 36%) than in LCIS-P (3 of 17; 18%); however, the difference was not statistically significant (x 2 test, P 5.26). A single case of LCIS-P showed no intraluminal necrosis, whereas all other LCIS variants with an upgrade showed necrosis (6 of 7; 86%). The presence of necrosis was not significantly associated with an upgrade (x 2 test, P 5.63). In 3 additional cases, DCIS was identified in the subsequent surgical specimen by hematoxylin-eosin morphology adjacent to the core biopsy site. Including all cases where a more significant lesion was present in the excisional specimen (7 invasive lobular carcinomas and 3 DCIS), the overall upgrade was 36% (10 of 28; Table 2). Overall, 61% (17 of 28) of LCIS variants were associated with malignancy in the ipsilateral breast, either DCIS or invasive carcinoma, at some point during the patient s clinical course. Focusing only on the associated invasive malignancy, 43% of LCIS variants (12 of 28) were associated with an invasive carcinoma in the same breast (Table 1). Eleven patients with LCIS variants diagnosed by core biopsy had no upgrade and no history of ipsilateral carcinoma and were representative of pure LCIS variants. One of these individuals (9%) was treated by mastectomy, and 10 patients (91%) were treated by conservative Table 2. Upgrade in Subsequent Surgical Excision of Lobular Carcinoma In Situ (LCIS) Variants Diagnosed in Core Biopsy Core Biopsy Diagnosis Upgrade to ILC in SSE, No. (%) Upgrade to DCIS in SSE, No. (%) Total Upgrade in SSE, No. (%) LCIS-N, n (36) 1 (9) 5 (45) LCIS-P, n (18) 2 (12) 5 (29) Total variant LCIS, n = 28 7 (25) 3 (11) 10 (36) Abbreviations: DCIS, ductal carcinoma in situ; ILC, invasive lobular carcinoma; LCIS-N, lobular carcinoma in situ with necrosis; LCIS-P, pleomorphic lobular carcinoma in situ; SSE, subsequent surgical excision. Arch Pathol Lab Med Vol 134, July 2010 LCIS Variants in Breast Cores Sullivan et al 1027

5 surgery, which included radiation treatment in 3 cases (Table 1). COMMENT In our retrospective study spanning 5 years, LCIS variants were more common than anticipated, representing 12% (9 of 75) of previously diagnosed solid DCIS cases. Most revised cases were LCIS variants that would require a complete surgical excision of the core biopsy site, similar to DCIS. Although LCIS-C diagnosed in core biopsy without discordant imaging is currently not considered a surgical disease, in the past, many were managed by surgical excision. The need for complete surgical excision of LCIS variants is supported by our results showing an upgrade in 25% of LCIS variants diagnosed in core biopsy and by the data previously presented by Chivukula et al, 13 who similarly reported a 25% upgrade in LCIS-P diagnosed in core biopsy. The upgrade rate seen in LCIS variants was also similar to that seen in the E-cadherin positive, solid DCIS core biopsies (26.7%) from our initial study group. The upgrades associated with LCIS variants in our study were limited to lesions presenting with microcalcifications, appeared to be associated with a younger age, and were more common in LCIS-N than in LCIS-P. The upgraded invasive cancers were all lobular types and were identified at an early stage, most commonly microinvasive. Based on our data, as well as other reports in the literature, 13 LCIS variants diagnosed on core biopsies are frequently associated with invasive carcinoma. This association may have 2 different implications. In our study, the invasive cancers were found in different quadrants, and their diverse histologic subtypes suggest that LCIS variants, similar to classic LCIS, are markers of risk for breast cancer. However, all the adjacent invasive carcinomas identified in our study as upgrades were of the lobular type, pointing to a possible precursor role of LCIS variants. The current treatment recommendations for management of patients with a diagnosis of breast carcinoma in situ on core biopsy vary depending on whether the diagnosis rendered is DCIS, LCIS-C, or an LCIS variant. A core biopsy diagnosis of DCIS requires complete surgical excision with negative margins and subsequent radiation therapy. At the opposite end of the spectrum, some studies show that pure LCIS-C may not require any excision when the pathologic and radiologic findings are concordant 14 and can be managed by observation and endocrine chemoprophylaxis. The recommendations for LCIS-P and LCIS-N are evolving, and there is no clear consensus, but complete surgical excision is currently recommended. 15 Although more research is needed to clarify the biologic potential of LCIS variants, given that their behavior is more aggressive and DCIS-like, achieving negative surgical margins seems like a reasonable goal. As LCIS variants are still not universally accepted entities in breast pathology, one approach frequently used is to designate these lesions as mixed carcinoma in situ with ductal and lobular features, a diagnosis that triggers the management required for DCIS. 4,15 However, unlike conventional DCIS, the clinical necessity of radiation therapy for variant LCIS lesions is not clear. Although the misinterpretation of LCIS variants as solid DCIS does not usually affect surgical management, it has important treatment implications with respect to radiation therapy because LCIS-C lesions are radiotherapy resistant. 16 However, despite the paucity of data on radiotherapy effect on LCIS variants and the lack of consensus recommendations, radiation therapy is often considered. The terminology of mixed carcinoma in situ with ductal and lobular features has been supporting this approach because it advocates the management required for DCIS. Although only prospective trials may be able to establish the value of radiation therapy for LCIS variants, at present, a correct pathologic classification of these lesions is the first step toward a better understanding of their behavior. Generous use of E-cadherin immunohistochemical stain may be appropriate on core biopsy specimens with solid carcinoma in situ to exclude LCIS variants unless definitive architectural and cytologic features of ductal differentiation are present. As better immunohistochemistry-derived data regarding LCIS variants emerge, more complete outcome data will become available to guide clinical recommendations. References 1. Rosen PP. Lobular carcinoma in situ and atypical lobular hyperplasia. In: Rosen s Breast Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009: Sneige N, Wang J, Baker BA, Krishnamurthy S, Middleton LP. 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Virchows Arch. 2000;436(5): Chivukula M, Haynik DM, Brufsky A, Carter G, Dabbs DJ. Pleomorphic lobular carcinoma in situ (PLCIS) on breast core needle biopsies: clinical significance and immunoprofile. Am J Surg Pathol. 2008;32(11): Hwang H, Barke LD, Mendelson EB, Susnik B. Atypical lobular hyperplasia and classic lobular carcinoma in situ in core biopsy specimens: routine excision is not necessary. Mod Pathol. 2008;21(10): Jacobs TW, Connolly JL, Schnitt SJ. Nonmalignant lesions in breast core needle biopsies: to excise or not to excise? Am J Surg Pathol. 2002;26(9): Rosen PP. Pathologic effects of therapy. In: Rosen PP, ed. Rosen s Breast Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009: Arch Pathol Lab Med Vol 134, July 2010 LCIS Variants in Breast Cores Sullivan et al