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Is Surgical Excision Necessary for the Management of Atypical Lobular Hyperplasia and Lobular Carcinoma In Situ Diagnosed on Core Needle Biopsy? A Report of 38 Cases and Review of the Literature

June 14, 2008

By Cangiarella, Joan Guth, Amber; Axelrod, Deborah; Darvishian, Farbod; Singh, Baljit; Simsir, Aylin; Roses, Daniel; Mercado, Cecilia

* Context.-Both atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) have traditionally been considered to be risk factors for the development of invasive carcinoma and are followed by close observation. Recent studies have suggested that these lesions may represent true precursors with progression to invasive carcinoma. Due to the debate over the significance of these lesions and the small number of cases reported in the literature, the treatment for lobular neoplasia diagnosed by percutaneous core biopsy (PCB) remains controversial. Objective.-To review our experience with pure LCIS or ALH diagnosed by PCB and correlate the radiologic findings and surgical excision diagnoses to develop management guidelines for lobular neoplasia diagnosed by PCB.

Design.-We searched the pathology database for patients who underwent PCB with a diagnosis of either pure LCIS or ALH and had subsequent surgical excision. We compared the core diagnoses with the surgical excision diagnoses and the radiologic findings.

Results.-Thirty-eight PCBs with a diagnosis of ALH (18 cases) or LCIS (20 cases) were identified. Carcinoma was present at excision in 1 (6%) of the ALH cases and in 2 (10%) of the LCIS cases. In summary, 8% (3/38) of PCBs diagnosed as lobular neoplasia (ALH or LCIS) were upgraded to carcinoma (invasive carcinoma or ductal carcinoma in situ) at excision.

Conclusions.-Surgical excision is indicated for all PCBs diagnosed as ALH or LCIS, as a significant percentage will show carcinoma at excision.

(Arch Pathol Lab Med. 2008;132:979-983)

Lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH) are high-risk breast lesions traditionally associated with an increased risk of malignancy in either breast. As compared to the risk in the general population, the risk of development of breast cancer is increased 4 to 5 times after a diagnosis of ALH and approximately 11 times after a diagnosis of LCIS.1-3 Analysis of Surveillance, Epidemiology and End Results data shows the minimum risk of developing invasive breast cancer after a diagnosis of LCIS to be approximately 7.1% at 10 years with equal predisposition for either breast.4 The traditional view of LCIS as a risk factor for the development of subsequent invasive carcinoma has been recently challenged. Current evidence utilizing molecular and genetic techniques suggests that LCIS and ALH may be indolent precursors of carcinoma rather than just markers of risk.5,6 This finding would lead to changes in the current management recommendations for patients diagnosed with ALH or LCIS, leading to altered treatment decisions. Currently, while most cases of LCIS diagnosed at surgical excision are managed conservatively with mammographic and clinical follow-up, the management guidelines for treatment of ALH or LCIS diagnosed by percutaneous core biopsy (PCB) has remained controversial. This is due to the small number of reports described in the literature that focus on the surgical follow-up of cases diagnosed as either ALH or LCIS on PCB.7-32 Also noted is the rarity of ALH or LCIS on PCB, with most series reporting incidences of less than 2%.7-8,11-12,16,18,28 We reviewed our experience with pure LCIS or ALH diagnosed by PCB and correlated these cases with radiologic findings and surgical excision diagnoses to develop management guidelines for lobular neoplasia diagnosed by PCB.

MATERIALS AND METHODS

The pathology database at New York University Hospitals Center was searched for patients who underwent PCB with a diagnosis of either pure LCIS or ALH and had subsequent surgical excision. Retrospective reviews of the pathology and radiology records were performed. Cases with secondary diagnoses of invasive cancer, ductal carcinoma in situ, or other high-risk lesions (atypical ductal hyperplasia, radial scar, papillary lesions) or cas es in which surgical excision follow-up was not available were excluded.

Core biopsies were performed with stereotactic or ultrasound guidance. Stereotactic biopsies were performed with either a 9- or 11-gauge vacuum-assisted biopsy device and ultrasound guided biopsies with a 14-gauge spring-loaded device. Specimen radiography was performed on all core specimens obtained for microcalcification. These were separated into formalin containers labeled ”with calcification” and ”without calcification.” Cores were embedded in paraffin, sectioned, and leveled mu5, and 3 slides were stained (levels 1, 3, and 5) with hematoxylin-eosin. None of the core biopsy specimens had E-cadherin staining. Surgical excision specimens were sectioned according to specimen type (mastectomy or segmental excision with or without needle localization), fixed in 10% formalin, paraffin embedded, and stained with hematoxylin-eosin. Correlation of pathologic findings with radiologic findings was performed.

Atypical lobular hyperplasia was defined by filling and distension of fewer than half of the terminal duct units of a lobule with uniform small cells. The cells were dyscohesive, evenly spaced, with round nuclei and minimal pleomorphism. Lobular carcinoma in situ was diagnosed when more than half of the acini in the terminal duct units were completely filled or distended.33

This study was approved by the New York University School of Medicine institutional review board.

RESULTS

Of 2439 patients who underwent PCBs, 38 (1.6%) with a diagnosis of ALH (18 cases) or LCIS (20 cases) were identified. All patients were women with a mean age of 55 years (range, 41-75 years). A family history of breast cancer was noted in 3 patients. Three patients had a history of breast cancer in the opposite breast. Mammography revealed findings in 33 cases including microcalcifi- cation in 30, an asymmetric density in 1, a spiculate mass in 1, and a well-circumscribed mass in 1. One case noted on mammogram (well- circumscribed mass) was also evident on ultrasound as a solid mass. Five cases were detected by ultrasonography only; circumscribed hypoechoic masses in 4 and a vague hypoechoic area in 1. At surgical excision, carcinoma (invasive carcinoma or ductal carcinoma in situ) was present at excision in 1 (6%) of the ALH cases and in 2 (10%) of the LCIS cases.

The radiologic abnormality in the ALH case that revealed carcinoma at excision was a 9-mm spiculate density. At surgical excision the spiculate mass was a 10-mm infiltrating ductal carcinoma. Lobular carcinoma in situ was present adjacent to this mass. At surgical excision, the remaining ALH cases showed fibrocystic changes in 7, residual atypical lobular hyperplasia in 7, and LCIS in 3. The clinical, radiologic, and surgical excision diagnoses for the ALH cases are summarized in Table 1.

The 2 LCIS cases that showed carcinoma at excision were for a vague hypoechoic area in 1 and microcalcifi- cation in the other. The hypoechoic area proved at surgical excision to be an 11-mm invasive lobular carcinoma with adjacent LCIS. The microcalcification case had ductal carcinoma in situ (DCIS), low grade, cribriform type, in combination with LCIS. Both pagetoid spread to lobules of DCIS and LCIS with retrograde extension into ducts was noted. Microcalcification was associated with LCIS. E- cadherin immunostaining on the surgical specimen was positive in areas of DCIS and negative in LCIS. At surgical excision, the remaining LCIS cases showed LCIS in 13, atypical lobular hyperplasia in 3, focal atypical ductal hyperplasia in 1, and fibrocystic changes in 1. The clinical, radiologic, and surgical excision diagnoses for the LCIS cases are summarized in Table 2.

All cases with a mammographic finding of calcification had calcifications identified on core biopsy. However, only in 11 cases (2 cases of ALH and 9 cases of LCIS) did the pathologic finding of ALH or LCIS account for the mammographic finding of calcification. In 1 case, LCIS accounted for the mammographic abnormality of an asymmetric density. In 16 cases of ALH and 11 cases of LCIS, the pathologic finding was incidental and did not account for the radiologic abnormality that was biopsied.

In summary, 8% (3/38) of patients with specimens from PCBs diagnosed as lobular neoplasia (either ALH or LCIS) showed carcinoma (invasive carcinoma or ductal carcinoma in situ) at excision.

COMMENT

Lobular carcinoma in situ was first described in 1941 as a proliferation of epithelial cells with lobules and terminal ducts within the breast that did not show extension beyond the basement membrane.34 Both ALH and LCIS are associated with an increased risk of carcinoma in either breast, 4 to 5 times increased risk after a diagnosis of ALH and approximately 11 times increased risk after a diagnosis of LCIS, as compared to the general population.1-3 The traditional view of LCIS as a risk factor for the development of subsequent invasive carcinoma has been recently challenged. Current evidence utilizing molecular and genetic techniques suggests that LCIS and ALH may be indolent precursors rather than solely a marker of risk.4,5 Studies supporting the concept of a precursor lesion have shown that in most cases subsequent carcinoma developed in the same site as the initial LCIS lesion.35-36 Other supportive evidence includes the suggestion of genomic clonality in paired samples from patients with LCIS and invasive lobular carcinoma.37 Current treatment recommendations for most cases of LCIS diagnosed at surgical excision are conservative, with mammographic and clinical follow- up. The management guidelines for treatment of ALH or LCIS diagnosed by PCB has, however, remained controversial secondary to the debate regarding the biologic significance of these lesions and the small number of published reports focusing on this uncommon finding.7-32 The finding of either ALH or LCIS on PCB is uncommon, occurring in only 0.34% to 2.9% of PCBs,17,29 with most series reporting incidences of less than 2%.7-8,11-12,16,18,28 Table 3 summarizes the published literature from series that reported the surgical excision findings from cases diagnosed as ALH or LCIS on PCB. These reports include cases for which the most significant pathologic finding on PCB was either ALH or LCIS, excluding cases that contained invasive/ in situ carcinomas or other high-risk lesions. From these accumulated data, ALH or LCIS at PCB is associated with a risk of finding carcinoma at surgical excision. This risk varies depending on the published series and differs between ALH and LCIS. Including our series, there are 24 published reports describing the findings at surgical excision for cases diagnosed as ALH on PCB.8-11,13-16,18-32 The range for finding carcinoma at excision is wide, from 0% to 67% (mean, 13%). Seven reports, representing 9% of the cases, do not show any evidence of carcinoma at surgery. For LCIS on core biopsy, the findings are similar. In the 22 published reports including our series,* carcinoma was noted in 0% to 50% (mean, 20%) of the cases at surgical excision. Five reports, representing 9% of the cases, did not show any evidence of carcinoma at surgery. The chance of finding carcinoma at excision is significant; carcinoma was noted in 13% of cases of ALH and 20% of cases of LCIS. While most authors recommend surgical excision for all cases diagnosed as ALH or LCIS on PCB,8,25,28,32,38 some recommend excision only when the diagnosis of LCIS is associated with a mass16 or with residual calcifications.11 Two studies found excision to be unnecessary. 15,31 Another study recommended excision when there was radiologic-pathologic discordance, when another high-risk lesion was present in the biopsy specimen, or when there were overlapping histologic findings, making distinction from DCIS difficult.9 Radiologic-pathologic concordance is essential for determining the necessary follow-up treatment for a patient who has undergone a PCB. Most cases of LCIS are thought to be an incidental finding in a specimen from a breast biopsy performed for another reason, without associated clinical or radiologic findings. However, several studies have described microcalcification in association with LCIS.9,13,39 One report found 2 forms of LCIS associated with calcifications: the classic type with uniform small cells and the pleomorphic type with larger cells and central necrosis.39 The pleomorphic type was indistinguishable radiographically from DCIS. At pathologic examination, this can be equally problematic.40 Pleomorphic LCIS shows tumor cells with a greater degree of pleomorphism, distinct nucleoli with commonly described calcification, and central necrosis complicating the distinction from DCIS.40 Staining with E-cadherin, a transmembrane glycoprotein involved in cell-to-cell adhesion, may be useful, as its expression has been shown to be lost in LCIS and invasive lobular carcinomas but not altered in DCIS or invasive ductal carcinomas.41 It has been suggested that the pleomorphic form of LCIS may be associated with a greater risk of developing an invasive carcinoma as compared to the classic form, and thus excision should be recommended if the pleomorphic type of LCIS is diagnosed on PCB.39 A recent report describes 18 cases of classic lobular carcinoma in situ with comedo-type necrosis.42 Pathologically, small- to-intermediate sized cells lacking pleomorphism are noted, distinguishing this entity from the pleomorphic variant of LCIS. Individual cell necrosis and comedo-type necrosis are present. The difficulty in distinguishing this lesion from DCIS is noted, and E- cadherin immunohistochemistry is paramount for an accurate diagnosis. In this report, 6 cases were diagnosed from core biopsy specimens. Subsequent surgical excision showed an upgrade to carcinoma in 67%. The authors emphasize the unknown natural history of LCIS with comedo-type necrosis and thus recommend excision when this lesion is detected at PCB.42

Mahoney et al28 studied the size of the core needle in determining whether larger bore core needles (11-gauge) would provide better histologic diagnostic accuracy, as * References 7-9, 11-13, 15-18, 20-25, 28-32. more tissue is sampled. The results did not show improvement; exclusive use of 11-gauge core needles still showed an upgrade rate to carcinoma in 19% of cases. Thus, while large needles obtain more tissue, they do not eliminate the possibility of upgrading to carcinoma. A recent study showed that the extent of lobular neoplasia in a core biopsy specimen may predict whether or not excision is required. 43 This study distinguished diffuse lobular neoplasia (>1 lobule per core affected) from focal lobular neoplasia (mu1 lobule per core) and found all upgrades to carcinoma to be associated with diffuse lobular neoplasia. Further studies with more patients are necessary to substantiate these findings.

In our series, 6% of cases diagnosed as ALH and 10% of cases diagnosed as LCIS on the basis of core biopsy material showed carcinoma at excision. The 3 cases in our study that were upgraded to carcinoma illustrate the problems with the diagnosis of ALH or LCIS in core biopsy specimens. Two cases showed a clear pathologic- radiologic discordance. The first case was a spiculate mass on mammography, and the second case was a suspicious hypoechoic lesion with ill-defined margins and posterior acoustic shadowing noted on sonography. In core needle biopsy specimens, the first lesion yielded a pathologic diagnosis of ALH and the second a diagnosis of LCIS. In both cases, the benign pathologic diagnosis did not explain (or correlate with) the highly suspicious imaging findings. Radiologic-pathologic concordance is essential in the management of patients who undergo PCB. The third upgraded case was for microcalcification. Excision showed LCIS but also DCIS of the low- grade type, with both pagetoid spread of DCIS into lobules and retrograde extension of LCIS into ducts. Microcalcification was associated with LCIS. The difficulty of distinguishing LCIS from DCIS, as noted above, illustrates the importance of E-cadherin immunostaining in making this distinction.

Our study is one of the larger series of PDBs with diagnoses of either atypical lobular hyperplasia or lobular carcinoma in situ and surgical excision follow-up. Our results support excision for ALH or LCIS diagnosed by PDB as the upgrade rate to carcinoma is not insignificant.

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Joan Cangiarella, MD; Amber Guth, MD; Deborah Axelrod, MD; Farbod Darvishian, MD; Baljit Singh, MD; Aylin Simsir, MD; Daniel Roses, MD; Cecilia Mercado, MD

Accepted for publication December 14, 2007.

From the Departments of Pathology (Drs Cangiarella, Darvishian, Singh, and Simsir), Surgery (Drs Guth, Axelrod, and Roses) and Radiology (Dr Mercado), New York University School of Medicine, New York.

The authors have no relevant financial interest in the products or companies described in this article.

Submitted for an abstract presentation at the 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, Tex.

Reprints: Joan Cangiarella, MD, Department of Pathology, NYU Hospitals Center, 530 First Ave, Skirball Suite 10U, New York, NY 10016 (e-mail: joan.cangiarella@med.nyu.edu).

Copyright College of American Pathologists Jun 2008

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