Original Articles. Clinical Implications of Margin Involvement by Pleomorphic Lobular Carcinoma In Situ

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1 Original Articles Clinical Implications of Margin Involvement by Pleomorphic Lobular Carcinoma In Situ Erinn Downs-Kelly, DO; Diana Bell, MD; George H. Perkins, MD; Nour Sneige, MD; Lavinia P. Middleton, MD N Context. The appropriate treatment for patients with pleomorphic lobular carcinoma in situ (PLCIS) is unknown. When diagnosed on core biopsy, excision is recommended; however, management of PLCIS when it involves margins has not been addressed. Objective. To evaluate the significance of PLCIS that is located close to, or at, a resection margin. Design. We identified 26 patients with resection specimens containing PLCIS, all of whom were offered chemoprevention and radiation therapy. The margin status in these patients was subdivided as PLCIS cells at the margin without obvious truncation of lesion; PLCIS less than or equal to 1 mm from, but not involving, the margin; PLCIS 1.1 to 2 mm from the margin; and PLCIS at least 2.1 mm from the margin. Results. Patient age ranged from 35 to 76 years (mean, 58 years), and length of follow-up ranged from 4 to 108 months (mean, 46 months). Six of the 26 patients (23%) received chemoprevention, 4 of 26 patients (15%) received radiation therapy, and 6 of 26 patients (23%) Invasive pleomorphic lobular carcinoma was first characterized by Dixon et al in 1982, 1 when he described a variant of invasive lobular carcinoma that did not fit one of the classic histologic patterns previously described. This entity was later well characterized, by Page et al 2 in 1987, as a neoplasm that had the typical architecture of an invasive lobular carcinoma but that was composed of discohesive neoplastic cells with markedly atypical nuclei rather than the classic low-grade nuclei that typify invasive lobular carcinoma. 3 6 Pleomorphic lobular carcinoma in situ (PLCIS), the cytologic in situ correlate of invasive pleomorphic carcinoma, has been recently described as a distinct entity with characteristic clinical, histologic, and imaging findings. 3 In contrast to classic lobular carcinoma in situ, PLCIS may be detected mammographically because of the presence of microcalcifications. 7,8 Histologically, PLCIS has been described as having the following characteristics: distended acini filled Accepted for publication July 30, From the Departments of Pathology (Drs Downs-Kelly, Bell, Sneige, and Middleton) and Radiation Oncology (Dr Perkins), The University of Texas M. D. Anderson Cancer Center, Houston. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Lavinia P. Middleton, MD, Department of Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd-Unit 85, Houston, TX ( lpmiddleton@mdanderson. org). received both. The remaining 10 patients received no further therapy. Pleomorphic lobular carcinoma in situ was at the margin in 6 of the 26 cases (23%), 1 mm from the margin in 7 of 26 cases (27%), 1.1 to 2 mm from the margin in 4 of 26 cases (15%), and was at least 2.1 mm from the margin in 9 of 26 cases (35%). In 1 of the 26 patients, recurrent PLCIS was identified 18 months after initial surgery, for an overall recurrence rate of 3.8%. All other patients were clinically and radiologically free of disease at last follow-up. Conclusions. This is the first series, to our knowledge, that evaluates margin status in patients with PLCIS and documents recurrence. Recurrent PLCIS was identified at a rate similar to low- or intermediate-grade ductal carcinoma in situ. Therefore, known methods of local control, including surgical excision with negative margins (2 mm), may be the appropriate treatment in these patients. (Arch Pathol Lab Med. 2011;135: ) with large, discohesive cells, with grade 2 to 3 nuclei that exhibit moderate to marked pleomorphism; distinct, small, prominent, or multiple nucleoli; eccentrically placed nuclei that are roughly 4 times the size of a lymphocyte; and abundant eosinophilic cytoplasm, with or without apocrine features The entity may or may not be associated with central necrosis or with microcalcifications or both and is frequently misclassified as ductal carcinoma in situ (DCIS). Importantly, in most cases, classic lobular carcinoma in situ or atypical lobular hyperplasia is found adjacent to the PLCIS. The biomarker expression is also distinct, with a relative (compared with classic lobular carcinoma in situ [LCIS]) decrease in estrogen and progesterone hormone receptor expression and a relative increase (compared with classic LCIS) in the Ki-67 labeling index and HER2 overexpression Immunohistochemical staining for E-cadherin can be used to differentiate ductal versus lobular carcinoma in situ because membranous staining is seen in most DCIS and negative staining is seen in lobular neoplasia Diffuse cytoplasmic immunostaining for P120 catenin without any appreciable cell membrane accentuation is considered to be characteristic of lobular phenotype Approximately 50% of PLCIS lesions described in the literature have an associated invasive pleomorphic lobular carcinoma. 9,12,20 Sneige et al 11 described a series of PLCIS cases, which was referred to as ductal-lobular carcinoma in situ, which had no Arch Pathol Lab Med Vol 135, June 2011 Treatment of Pleomorphic Lobular Carcinoma In Situ Downs-Kelly et al 737

2 associated invasive pleomorphic lobular carcinoma and compared those cases to cases of PLCIS with an associated invasive pleomorphic lobular component. The authors 11 found that the histomorphologic and biomarker characteristics were similar across subsets, suggesting that the in situ and invasive lesions were indeed related. Emerging molecular data have identified concomitant genetic changes that support the hypothesis that PLCIS may be a precursor lesion to invasive pleomorphic lobular carcinoma. 21 Additionally, PLCIS has been found to have genetic changes that are analogous to those of DCIS. 21 Although classic LCIS is considered a marker of increased risk and, in some instances, a nonobligate precursor for the development of invasive breast carcinoma, 22 the natural history of PLCIS is not known, and therefore, its management has not been well characterized. Given that PLCIS is frequently associated with an invasive carcinoma, treatment has been dependent on the size of the invasive component. When PLCIS is present on core needle biopsy, most pathologists recommend excision. However, treatment recommendations are not uniform, and the significance of PLCIS at a margin of resection is unknown, raising questions as to whether reexcision to obtain negative margins ($2 mm) is appropriate or whether there is a role for radiotherapy. In this series, we describe the outcome of patients with PLCIS at or near a margin in resection specimens and provide rationale for obtaining negative margins (,2 mm). MATERIALS AND METHODS We identified cases in the surgical pathology files of the Department of Pathology at the University of Texas M. D. Anderson Cancer Center (Houston) with a diagnosis of PLCIS that was at or near a margin in resection specimens and that included a lumpectomy, a segmental mastectomy, or both, including both consultations and in-house cases. Inclusion criteria included (1) the lesion had the characteristic histomorphologic findings of PLCIS, including grade 2 to 3 nuclei, with moderate to marked pleomorphism; distinct, small, or prominent nucleoli; and eccentrically placed nuclei that were roughly 4 times the size of a lymphocyte; (2) the lesion was treated with excision; and (3) there was a complete absence of E-cadherin (dilution 1:100; formerly Zymed, now Invitrogen Corporation, Carlsbad, California) immunoreactivity within the PLCIS. An additional 6 cases with an invasive component, classified as either suspicious for invasion, microinvasion (#0.1 cm; T1mic), or an invasion measuring 0.1 cm but no more than 0.5 cm (T1a) were included, provided that the invasive component was greater than 1 cm from the final margin of resection. Patients with PLCIS who underwent total or modified radical mastectomy were excluded from the study group. The patient s electronic medical record was assessed to obtain radiographic data and clinical follow-up. In certain instances, follow-up information was sought from outside contributing pathologists and clinicians. This project was approved by our Institutional Review Board Protocol Committee (RCR Lab ). The resection specimens were examined intraoperatively, frequently with the assistance of specimen radiography, and margins were extensively sampled. The margin status of the specimens was subdivided as follows: (1) PLCIS cells at the margin, with or without obvious truncation of the lesion; (2) PLCIS cells that are less than, or equal to, 1 mm from, but not involving, the margin; (3) PLCIS cells that are 1.1 to 2 mm from the margin; and (4) PLCIS cells that are at least 2.1 mm from the margin. Immunohistochemistry was performed using the avidinbiotin technique (LSAB2 peroxidase kit, Dako, Carpinteria, California) with recommended dilutions. The immunoreaction was visualized with a 3,39-diaminobenzidine chromogen (Dako), and the slides were counterstained using Mayer hematoxylin (Sigma Chemical Company, St Louis, Missouri). E-cadherin (dilution 1:100; Invitrogen) was interpreted as either negative or positive based on the absence or presence of membranous immunoreactivity in the cells of interest, with evaluation of appropriate internal controls. Ki-67 (dilution 1:100; Dako) was evaluated in the lesional tissue at or near the margin with the premise that the cell proliferation would be greatest at the leading edge of the tumor. RESULTS We identified 20 patients with PLCIS that were treated with either segmental mastectomy or lumpectomy. Photomicrographs depicting the typical histology of the cases are presented in Figure 1. An additional 5 patients were included who had microinvasion (invasion measuring #1 mm). Retrospective evaluation of 1 additional patient with PLCIS revealed a 3-mm focus of invasion. The various margin status groups, their respective clinicopathologic findings, and their follow-up results are presented in Table 1. Although the focus of this study was the evaluation of the margin status of patients with PLCIS, an important finding (and diagnostic aid) was that 95% of the cases had classic LCIS, either identified admixed with the lesion or in adjacent sections (Figure 2). Mammographic abnormalities were present in all cases (100%; 26 of 26), with suspicious or indeterminate calcifications being the most common finding (85%; 22 of 26). Histologically, 15 of 26 cases (58%) had associated comedo-type necrosis, 25 of 26 (96%) had microcalcifications associated with the PLCIS, whereas an additional 10 of 26 cases (38%) also had microcalcifications associated with fibrocystic changes. Pleomorphic lobular carcinoma in situ was the most significant lesion in 20 of 26 patients (77%), with areas suspicious for microinvasion, areas of T1mic, or areas of T1a present in 6 of 26 cases (23%). In all cases that contained areas suspicious for microinvasion, T1mic, and T1a, carcinomas were greater than 1 cm from the final margin of resection. Patient age ranged from 35 to 76 years (mean, 58 years), with length of follow-up ranging from 4 to 108 months (mean, 46 months). All lesions were positive for estrogen receptor, and patients were offered chemoprevention (CP), radiation therapy (XRT), or both CP and XRT. Six of 26 patients (23%) received CP, 4 of 26 (15%) received XRT, and 6 of 26 (23%) received both CP and XRT. The remaining 10 patients received no additional therapy (38.5%). Of the 6 cases that received both CP and XRT, 5 patients (83%) had been diagnosed as either T1mic, T1a, or with areas suspicious for microinvasive carcinoma, and 1 case had been previously categorized as DCIS. Of the 4 patients that received XRT, 2 (50%) had been erroneously designated as having DCIS on core needle biopsies, and 1 patient had an area suspicious for microinvasion. Pleomorphic lobular carcinoma in situ was at the margin in 6 of 26 cases (23%), 1 mm from the margin in 7 of 26 cases (27%; Figure 3), 1.1 to 2 mm from the margin in 4 of 26 cases (15%), and was at least 2.1 mm from the margin in 9 of 26 cases (35%). Ki-67 immunoreactivity in cells at or near the margin of resection ranged from 1% to 30% (mean, 7.5%) across all margin groups (Figure 4). Recurrent PLCIS was identified in 1 patient with a positive margin (overall recurrence regardless of treatment, 3.8%) (Table 2). This patient had an interval mammogram at 12 months that showed no abnormalities 738 Arch Pathol Lab Med Vol 135, June 2011 Treatment of Pleomorphic Lobular Carcinoma In Situ Downs-Kelly et al

3 Figure 1. A, Histomorphologic features of pleomorphic lobular carcinoma in situ; lobules are expanded by enlarged, discohesive cells. B, Corresponding E-cadherin stain result is negative in the cells of the pleomorphic lobular carcinoma in situ and immunoreactive in the adjacent ductal epithelium. C, Frequently there is central necrosis. D, High-power magnification shows that the tumor cells show moderate to marked nuclear pleomorphism, eccentrically placed nuclei, and an intracytoplasmic mucin droplet characteristic of pleomorphic lobular carcinoma in situ (hematoxylin-eosin, original magnifications 3100 [A], 3200 [C], and 3400 [D]; original magnification 3100 [B]). and developed new mammographically suspicious calcifications at the previous surgical resection site at 19 months of follow-up. Stereotactic biopsy of these calcifications showed recurrent disease, and the patient was subsequently treated with a mastectomy. All other patients were clinically and radiologically free of disease at the time of last follow-up. COMMENT The goals of treating carcinoma in situ are to prevent the development of a same-site invasive carcinoma, to obtain a favorable cosmetic outcome that is acceptable to the patient, and to avoid unnecessary toxicity. Many large, randomized trials have addressed the treatment of DCIS,23 26 with the findings guiding the standard of care. For classic LCIS diagnosed on core needle biopsy, excision is recommended when there is an associated mass lesion; when there is a histologic and mammographic discordance; when residual, worrisome calcifications remain; or when the patient has another associated, high-risk lesion In patients with PLCIS, the conventional wisdom has been to recommend excision when diagnosed Arch Pathol Lab Med Vol 135, June 2011 on core needle biopsy. However, that recommendation is pragmatic, with little supporting data.21 In addition, the question of the importance of margin status in the excised specimen of PLCIS has not been addressed to date, to our knowledge. The histomorphology of PLCIS has been described by both Frost et al9 and Shin et al10 without a focus on treatment. Frost et al9 described the lesion as being composed of one or multiple distended lobules; large, discohesive cells with irregularly shaped nuclei and abundant eosinophilic cytoplasm; and either single or multiple nucleoli features that could be misdiagnosed as DCIS. The authors9 also noted the frequent association with necrosis, calcifications, and invasive pleomorphic lobular carcinoma. Shin et al10 described 21 cases of florid LCIS with extreme glandular enlargement, necrosis, and associated calcifications. Concomitant invasive carcinoma was present in 57% of the cases, and complete absence of E-cadherin was seen in 86% of the cases. Loss of heterozygosity for loci near the E-cadherin gene was identified in 94% of their cases. The authors concluded that this was a distinct entity, morphologically similar to Treatment of Pleomorphic Lobular Carcinoma In Situ Downs-Kelly et al 739

4 Case No. Table 1. Clinicopathologic Features of the 26 Patients Undergoing Segmental Mastectomy for Pleomorphic Lobular Carcinoma in Situ (PLCIS) Radiologic Findings Age, y Prompting Initial Biopsy 1 61 MMG: suspicious Ca 2+ and increased density (ACR 4) Margin Status With Respect to PLCIS Additional Treatment a mm XRT NRED (104) Follow-up Findings (mo) 2 66 MMG: suspicious Ca 2+ (ACR 4) mm CP NRED (84) 3 62 MMG: suspicious Ca 2+ (ACR 4) At margin without truncation of lesion CP Negative (7 and 12), MMG (19), MMG with new suspicious Ca 2+ in prior surgical scar site, consistent with recurrent, biopsy-proven PLCIS 4 58 MMG: amphorous Ca 2+ (ACR 0) #1 mm CP NRED (76) 5 47 MMG: suspicious Ca 2+ (ACR 4) #1 mm No NRED (30) 6 60 MMG: benign Ca 2+ (ACR 0); US: hypoechoic mass corresponding to palpable lesion At margin without truncation of lesion No NRED (25) 7 66 MMG: suspicious Ca 2+ (ACR 4) At margin without truncation of lesion XRT and CP NRED (58) 8 71 MMG: suspicious Ca 2+ (ACR 4) #1 mm XRT and CP NRED (47) 9 48 MMG: indeterminate Ca 2+ (ACR 6) #1 mm XRT NRED (35) MMG: suspicious Ca 2+ (ACR 4) mm XRT and CP NRED (89) MMG: suspicious Ca 2+ (ACR 4) At margin without truncation of lesion No NRED (29) MMG: indeterminate Ca 2+ (ACR 3).2.1 mm XRT and CP NRED (78) MMG: suspicious Ca 2+ (ACR 5).2.1 mm XRT and CP NRED (108) MMG: benign Ca 2+ (ACR 2); US: fibroadenoma corresponding to palpable lesion.2.1 mm CP NRED (88) MMG: suspicious Ca 2+ (ACR 4) #1 mm CP NRED (26) MMG: suspicious Ca 2+ (ACR 4).2.1 mm XRT NRED (74) MMG: architectural density.2.1 mm No NRED (37) MMG: suspicious Ca 2+ (ACR 4) At margin without truncation of lesion No NRED (20) MMG: benign Ca 2+ (ACR 2) #1 mm CP NRED (82) MMG: suspicious Ca 2+ (ACR 4).2.1 mm XRT and CP NRED (28) MMG: suspicious Ca 2+ and,1 mm No NRED (12) increased density (ACR 4) MMG: suspicious Ca 2+ (ACR 4) 1.5 mm No NRED (8) MMG: pleomorphic Ca 2+ (ACR 0) At margin No NRED (1) MMG: suspicious Ca 2+ (ACR 4).2.1 mm XRT NRED (8) MMG: suspicious Ca 2+ (ACR 6).2.1 mm No NRED (13) MMG: suspicious Ca 2+ (ACR 4).2.1 mm No NRED (9) Abbreviations: ACR, American College of Radiology Bi-Rads (Breast Imaging and Reporting Data System) category; Ca 2+, calcifications; CP, chemoprevention; MMG, mammography; NRED, no radiologic evidence of disease; US, ultrasound; XRT, radiation therapy. a No indicates no further treatment after segmental mastectomy. solid, low- to intermediate-grade DCIS, but separated by negative E-cadherin immunoreactivity. Fadare et al 30 described the clinicopathologic features of 18 cases of LCIS with comedo-type necrosis. The authors 30 principal inclusion criteria included the identification of 1 or more foci that differed from conventional LCIS by the presence of central, comedo-type necrosis and the lack of E- cadherin immunoreactivity within the lesion. Twelve of the lesions (67%) were identified in excisional biopsy or mastectomy specimens, whereas 6 of the lesions (33%) were identified in incisional or core biopsies. Twelve of the 18 cases (67%) had an associated invasive carcinoma. Follow-up was available in 1 case, initially diagnosed as DCIS and treated with XRT. The patient developed recurrent LCIS with necrosis after 7 years. Given the higher-than-expected rate of associated invasive carcinoma with this lesion, the authors 30 recommended excision of the lesion when present on core biopsy or at the margin of resection. Sapino et al 8 described 10 cases of LCIS that were histologically composed of intermediate-sized nuclei and contained necrosis and associated calcifications and were thus mammographically detectable. All of the lesions were negative for E-cadherin and positive for c-erbb2. Five of the lesions were purely in situ, whereas 4 cases had additional invasive lobular carcinoma with pleomorphic features in addition to the in situ component. The authors 8 point out the multicentricity of the in situ component, identified in 7 patients who had undergone simple mastectomy (4 of these patients had an invasive carcinoma, 3 of which had axillary nodal metastases). Two patients with pure in situ disease were treated with wide excision, with no evidence of disease on follow-up at 2 and 11 months. In contrast to this study, wherein all patients were definitively treated with segmental mastectomy, Sapino et al 8 suggested that simple mastectomy may be an appropriate treatment because this variant of LCIS approaches DCIS in necrosis, calcifications, and cytologic pleomorphism. Chivukula et al 31 evaluated the histologic and immunohistochemical profile of pure PLCIS diagnosed on core needle biopsy and presented follow-up data on the rate of upgrading the lesion; residual carcinoma was found in 83% of cases (carcinoma in situ, n 5 10; invasion, n 5 3). Although the current study included only PLCIS cases that were localized and would, therefore, justify local excision, this group actually represents a subset of our patients diagnosed and treated 740 Arch Pathol Lab Med Vol 135, June 2011 Treatment of Pleomorphic Lobular Carcinoma In Situ Downs-Kelly et al

5 Figure 2. A, The upper-left corner of the photomicrograph shows pleomorphic lobular carcinoma in situ, whereas the lower-right corner shows classic lobular carcinoma in situ. B, Pleomorphic nuclei that are typically 4 times the size of a lymphocyte, with prominent nuclei. The contrasting, classic lobular carcinoma in situ inset has monomorphic nuclei that are approximately 1.5 times the size of a lymphocyte and lack discernable nucleoli (hematoxylin-eosin, original magnifications 3100 [A] and 3200 [B]). Figure 3. Example of pleomorphic lobular carcinoma in situ that is 1 mm from, but not involving, the inked margin of resection (hematoxylineosin, original magnification 3100). Figure 4. Ki-67 labeling of approximately 30% of the pleomorphic lobular carcinoma in situ cells in the field; inset shows the lack of E-cadherin immunoreactivity in the same lesion with appropriate internal control in the adjacent ductal epithelium (immunohistochemical stain, original magnification 3100). with PLCIS. Most patients with PLCIS seen at this institution have been treated with total mastectomy because of its frequent diffuse, multicentric distribution and frequent association with an invasive carcinoma (L.P.M., unpublished data, 2009). The above descriptions of PLCIS highlight the frequent association with an invasive component and the need for excision with thorough sampling of the excised specimen when diagnosed on core needle biopsy. This current study also identified an invasive component in 23% of the cases diagnosed as carcinoma in situ on core biopsy. In one instance, the invasion was identified retrospectively, serving as a reminder that identifying microinvasion in a background of extensive carcinoma in situ is challenging, even for the most experienced pathologist. This current series is the first, to our knowledge, to address margin status in relation to PLCIS. Because the proliferation rate, as assessed by Ki-67 staining, was similar across all margin groups, that marker does not appear to identify Arch Pathol Lab Med Vol 135, June 2011 cases with a higher risk of recurrence. Some emerging molecular studies suggest that the genetic alterations present in PLCIS are more akin to DCIS than LCIS.13,21 Acknowledging that our series is relatively small and that our clinical follow-up is just more than 2 years, if our findings are supported in larger studies, then treating PLCIS as DCIS is treated (2-mm negative surgical margins, with or without the addition of XRT) would be prudent. A comparison of similar-sized lesions of DCIS, both low and high grade, with a cohort of PLCIS patients would be ideal. However, such a study is not practical because the standard of care dictates that DCIS treated with breastconserving surgery be followed by XRT. The randomized trials, National Surgical Adjuvant Breast Project protocol B17 (NSABP B17)24 and the European Organization for Research and Treatment of Cancer protocol (EORTC 10853)25 have identified the risk of recurrent DCIS as 1% to 2% per year in patients with negative margins, low- to intermediate-grade DCIS, and no adjuvant XRT, whereas Treatment of Pleomorphic Lobular Carcinoma In Situ Downs-Kelly et al 741

6 Table 2. Margin Status: No. of Cases (%), N = 26 Clinicopathologic Features of the 26 Patients With Pleomorphic Lobular Carcinoma In Situ (PLCIS) Undergoing Segmental Mastectomy Age Range, y (mean, y) No. (%): Radiographic Findings Ki-67 Range, % (mean, %) No. of Patients: Treatment Follow-up Range, mo (mean, mo) 1 12 (6.5) 4: no treatment 9 42 (21.8); 1 recurrence PLCIS at margin: 6 (23) (60.8) 4 of 6 (66.6): suspicious Ca 2+ 2 of 6 (33.3): benign Ca 2+ 1: CP 1: CP and XRT at 19 mo (patient received only CP) PLCIS,1 mm from margin: 7 (27) 1 30 (10.3) 2: no treatment (33.3); AARFD (58.1) 4 of 7 (57): suspicious Ca 2+ 3: CP 1 of 7 (14): indeterminate Ca 2+ 2 of 7 (28.6): benign findings 1: CP and XRT 1: XRT PLCIS mm from margin: 4 (15) PLCIS $2.1 mm from margin: 9 (35) 2 5 (4.5) 1: no treatment (63.8) 4 of 4 (100): suspicious Ca 2+ 1: CP 1: CP and XRT 1: XRT 7 88 (59); AARFD 1 15 (7) 3: no treatment (52.8); AARFD (52.6) 5 of 9 (55): suspicious Ca 2+ 3: CP and XRT 1 of 9 (11): benign Ca 2+ 1: CP 1 of 9 (11): lobular mass 2: XRT 1 of 9 (11): indeterminate Ca 2+ 1 of 9 (11): architectural density Abbreviations: AARFD, all alive and radiographically free of disease; Ca 2+, calcifications; CP, chemoprevention; XRT, radiation therapy. in this current series, recurrent PLCIS was also identified at a similar rate, suggesting that the risk for recurrent PLCIS is at least similar to low- to intermediate-grade DCIS. Known methods of local control, including surgical excision with negative margins (2 mm), are, therefore, likely to be the appropriate treatment in patients with PLCIS at or near the margin of resection. Traditionally, the argument against XRT in LCIS has been that this lesion is not radiosensitive. However, given the high-grade cytology and frequently increased Ki-67 proliferative index, 11 PLCIS may be more radiosensitive than classic LCIS, and perhaps, some benefit from XRT maybe derived. Future studies are needed to address the efficacy of radiotherapy in these lesions. Deciding on the best therapy for patients diagnosed with PLCIS of the breast is an uncommonly encountered issue that remains controversial. The limitations of this study are acknowledged in that this was a retrospective study with only 26 patients and 1 recurrence and a median follow-up of 33 months. 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