Lobular neoplasia of the breast: an update.
Abstract: * Context.--Lobular neoplasias (LNs) of the breast include atypical lobular neoplasia and lobular carcinoma in situ. Recent evidence suggests that LN is not only a risk factor for invasive lobular carcinoma, but is also a nonobligate precursor. Pleomorphic lobular carcinoma in situ (PLCIS) is a subtype of LN that has high-grade nuclei and other features that may mimic high-grade ductal carcinoma in situ. The management and follow-up of patients diagnosed with LN on core biopsy is a current issue of debate. However, recent genomic and molecular studies have identified candidate genes that may be important in understanding the pathogenesis of atypical lobular neoplasia and lobular carcinoma in situ, and thus may lead to other therapeutic interventions.

Objective.--To review the literature on LN of the breast and discuss current issues in the diagnosis and management of this entity, with particular attention to the relatively newly recognized lesion PLCIS. Because the management of PLCIS varies from the other LN lesions, the recognition of PLCIS by the pathologist is necessary. Current issues in the molecular pathogenesis of LN are also presented.

Data Sources.--Extensive review of the literature. Hematoxylin-eosin-stained and immunohistochemical stained tissue from the author's personal collection.

Conclusions.--Although morphology and immunohistochemical stains, such as E-cadherin, are important in the diagnosis and understanding of LN, genomic and molecular studies may guide the way these lesions are handled in the future. Recognizing PLCIS is important both for patient management and for our future understanding of LN pathogenesis.
Article Type: Report
Subject: Breast cancer (Risk factors)
Breast cancer (Development and progression)
Breast cancer (Diagnosis)
Breast cancer (Genetic aspects)
Immunohistochemistry (Usage)
Immunohistochemistry (Analysis)
Authors: Contreras, Alejandro
Sattar, Husain
Pub Date: 07/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: July, 2009 Source Volume: 133 Source Issue: 7
Accession Number: 230152043
Full Text: In situ lobular neoplasia (LN) of the breast was first documented by Ewing (1) in 1919 in 2 photomicrographs with the captions "atypical proliferation of acinar cells" and "precancerous changes ... atypical proliferation in a segment of a duct." Decades later, Foote and Stewart (2) characterized LN as a monomorphic population of cells that arise from and expand the terminal duct lobular unit and spread through the ductal system in a pagetoid manner. They noted that such lesions were not appreciated on clinical or gross examination and were often multicentric and bilateral. Although Foote and Stewart (2) recognized a spectrum of LN, they felt that even the slightest degree of this process constituted "an extreme hazard." Hence, any extent of LN was considered malignant and warranted complete mastectomy. (2)

Our understanding of LN remained unchanged for almost 40 years, until Haagensen et al (3) published a report on a series of 211 patients with lobular carcinoma in situ (LCIS) without associated invasive carcinoma. They reiterated many of the features originally described by Foote and Stewart (2) and expanded on the clinical features, noting an overall incidence of 3.8%, with most of these cases occurring in pre-menopausal women. In stark contrast to Foote and Stewart, however, Haagensen et al (3) suggested that LN was a benign proliferation that portended increased risk for subsequent carcinoma in either breast, and hence required monitoring with close follow-up. (3) Central to their argument were follow-up data that showed an increased risk for development of invasive carcinoma (overall 17%) spread across a long interval of time (up to 25 years). More importantly, this risk applied with relatively equal frequency to both the ipsilateral and contralateral breast. As a result, they suggested that such lesions be termed lobular neoplasia rather than carcinoma in situ. This study was widely accepted and resulted in a major shift in our understanding of the biologic potential of LN. Lobular neoplasia quickly became viewed as a risk factor for subsequent breast carcinoma in either breast instead of a nonobligate precursor for invasive disease. Shortly thereafter, sentinel work by Page et al (4,5) documented the relative risk of these lesions and correlated this risk to the extent of LN.


The argument that LN was not a precursor to invasive disease was based on several important observations. The first was the relatively low frequency of development of invasive carcinoma, along with the long lag time in those who ultimately developed invasive disease. The second was the development of disease in either breast with relatively equal frequency. If LN was a precursor to invasive disease, then how could its presence in one breast result in a cancer in the opposite breast? The third was the observation that the invasive carcinoma following LN was equally likely to be ductal or lobular. If it was truly a precursor, then one would expect LN to develop solely into invasive lobular carcinoma.


More recent work by Page et al, (6) along with molecular evidence, has raised doubts about these initial observations, once again shifting our understanding of the biologic nature of this peculiar lesion. Page et al (6) reviewed follow-up data on 261 benign breast biopsies with atypical lobular hyperplasia (ALH) taken from 252 women between 1950 and 1985. Their findings showed that invasive carcinoma arising after a diagnosis of ALH was 3 times more likely to arise in the breast diagnosed with ALH than in the opposite breast, and that this invasive carcinoma was much more likely to be lobular than ductal. In addition, molecular studies have shown that the genetic profiles of LCIS and synchronous invasive lobular carcinoma are often similar to each other. (7,8) These findings suggest that some LN lesions are indeed nonobligate precursors to invasive lobular carcinoma.


Lobular neoplasia exhibits a spectrum of acinar involvement that can be subdivided into LCIS and ALH. Criteria for the diagnosis of LCIS include characteristic nuclear, cytologic, and architectural features. More specifically, LCIS is classified as a monotonous, discohesive proliferation of round, slightly hyperchromatic cells that are evenly spaced and distend and fill acinar lumina (Figure 1, A and B). Partial involvement of acini, defined as less than one-half of the acini of an involved lobule, is classified as ALH (Figure 1, C and D). More often than not, the cells of LN are also present interspersed between the basement membrane and native epithelium of ducts (pagetoid spread). When present alone, this latter finding is classified as ALH by some authorities and LCIS by others. (9)

In most cases of LN, at least some of the cells have characteristic intracytoplasmic vacuoles, often with eosinophilic mucin globules. The cells of classic LN have been divided into 2 subtypes: those exhibiting scant cytoplasm and nuclei roughly 1.5 times the size of a lymphocyte (type A) and those with more abundant cytoplasm and somewhat larger nuclei (type B). (10) This distinction is important in defining the cytologic spectrum of LN; however, it bears no documented clinical significance. (11)

Some authorities advocate using the term LN for the entire spectrum of ALH/LCIS. This is appealing in that it avoids the term carcinoma for a lesion that is, for the most part, a risk factor for carcinoma. However, the established variation in relative risk for subsequent development of carcinoma between ALH (relative risk 5.5) and LCIS (relative risk 8-10), (4,5) along with more recent studies showing differences between molecular alterations in ALH and LCIS, (12) supports maintaining this subclassification.



Recently, a pleomorphic subtype of LN (pleomorphic lobular carcinoma in situ [PLCIS]) has become more widely recognized. (13,14) This form exhibits larger cells with the characteristic discohesive nature of LN but with pleomorphic nuclei, typically grade 3 using modified Scarff-Bloom-Richardson grading criteria, and more obvious nucleoli (Figure 2, A and B). (15) These cells often exhibit apocrine differentiation and can show necrosis and microcalcifications mimicking high-grade ductal carcinoma in situ (DCIS; Figure 2, C). (16) Pleomorphic lobular carcinoma in situ is best recognized by its association with classic LN in the nearby vicinity. The frequent coexistence of these 2 subtypes of LN suggests a common genetic pathway shared by classic and pleomorphic LN. In fact, recent molecular profiling studies comparing invasive classic and pleomorphic lobular carcinomas support this notion as well. (17,18)


Distinguishing classic LCIS from DCIS is essential, given that LN generally dictates close follow-up and chemoprevention with tamoxifen, whereas DCIS requires eradication with surgery and radiotherapy. Most cases of LCIS are readily distinguished from low-grade DCIS with hematoxylin-eosin stain. In ambiguous cases, use of E-cadherin immunostain is useful to distinguish these 2 entities. (19-21) Lobular neoplasia generally exhibits loss of membrane staining due to inactivation of the E-cadherin gene, located on chromosome 16q (Figure 3, A). (22,23) Ductal carcinoma in situ, on the other hand, lacks this inactivation, and hence retains linear, membranous staining (Figure 3, B). E-cadherin stains should be interpreted in the context of morphologic features, because rare cases of ductal carcinoma in situ with reduced or complete loss of E-cadherin expression have been reported, and aberrant expression of E-cadherin in LN has been reported as well. (19,20,24-27)


In rare cases (10%-15%), E-cadherin stain may be equivocal. These cases are often categorized as "mammary carcinoma in situ with mixed ductal and lobular features" and are managed as ductal carcinoma. In such cases, p120 catenin has been suggested as a useful immunomarker for LN. The p120 catenin binds E-cadherin on the internal aspect of the cell membrane, aiding in stabilization of the E-cadherin complex. (28-32) Disregulation of the E-cadherin complex in LN results in cytoplasmic redistribution of p120 catenin. (33) Ductal carcinoma in situ maintains the E-cadherin complex, and hence p120 catenin remains membranous in distribution.

Finally, expression of high-molecular weight keratins may also be useful in characterizing LN. The clone 34bE12 (cytokeratins 1, 5, 10, and 14) is commonly expressed by LN and is usually absent or minimally expressed by ductal carcinoma. (34,35) However, optimal use of this antibody requires heat-retrieval tissue preparation, because other methods may result in false-negative staining. (34,35)


Pleomorphic lobular carcinoma in situ and high-grade DCIS are currently managed similarly, and hence distinguishing between these 2 entities is not of the clinical import discussed above. Again, PLCIS is most readily identified by the presence of classic LCIS in the nearby vicinity. Like LCIS, PLCIS exhibits loss of E-cadherin staining (Figure 2, D) and cytoplasmic redistribution of p120 catenin, and hence these 2 stains are useful to confirm a suspected diagnosis. (36)


Evidence suggesting that some LN is a nonobligate precursor for invasive carcinoma has raised concerns about the need for follow-up surgical excision when LN is present on core needle biopsy. Studies vary in detection rates of a more advanced lesion (up to 20%) when follow-up surgical excision is performed after diagnosis of LN on biopsy. (37-45) Although many of these studies are limited by size and selection bias, they do provide some practical guidelines that suggest when a more advanced lesion is most likely to be detected. Excision is prudent when there is discordance between pathologic changes present on biopsy and radiographic or clinical findings, when LN with atypical features is present (eg, PLCIS), or when LN is associated with another generally excised lesion (eg, atypical ductal hyperplasia) in the core.

The role of magnetic resonance imaging screening in patients diagnosed with LN on needle biopsy is unclear. However, one recent, institutional, retrospective study showed detection of subsequent cancer in a small subset of patients previously diagnosed with LCIS who underwent further screening by magnetic resonance imaging. (46) No cases of cancer on magnetic resonance imaging-generated follow-up biopsies were found in patients previously diagnosed with ALH. Further studies in this area are warranted.


The future management of LN may rely on dissecting the molecular pathways involved in the development of these lesions. Genomic and molecular studies have provided necessary insight into the pathogenesis and biology of LN. Atypical lobular hyperplasia exhibits more genomic alterations compared with LCIS, suggesting that they represent distinct biologic entities. (12) However, both ALH and LCIS exhibit copy number gains in regions that harbor the AKT1 and CSF1R genes. These genes can disrupt cell polarization, (47,48) possibly effecting an early common molecular pathway involved in LN maintenance. Only LCIS shows a gain in copy number of a region harboring the CCAAT/enhancer-binding protein (CEBP) beta, which may influence LCIS progression through its effect on cell proliferation and differentiation.

The loss of E-cadherin is not sufficient for tumorigenesis, as highlighted by the requirement for p53 inactivation in murine invasive lobular carcinoma development. (49) Thus, loss of other tumor-suppressor genes may be involved in the pathogenesis of LN. Interestingly, CCCTCbinding factor (CTCF) and Dipeptidase 1 (DPEP1), both candidate tumor-suppressor genes, were found to have decreased expression in LCIS versus normal breast lobules. (50) Both genes are found on chromosome 16q.

Whether the loss or gain of the above genes influences initiation or promotion of LN remains to be determined. However, these findings should encourage further identification of candidate tumor-suppressor genes or oncogenes through a targeted search in areas of common genomic aberrations.


Our understanding of the clinical outcomes and biology of LN has evolved during the past century, and it will continue to evolve with the combined, synergistic efforts of both basic and translational research. The histologic (hematoxylin-eosin) and immunohistochemical (E-cadherin, p120) characterizations of LN were important first steps in defining and understanding the pathogenesis of these lesions. Furthermore, the identification of PLCIS as a distinct, aggressive subtype of LN has increased the spectrum of lesions within LN. Given the histologic and biologic heterogeneity of LN, it is likely that genomic and molecular studies will guide our future handling of these lesions both pathologically and clinically. In summary, although not as much is known about LN as its ductal counterparts, namely, ADH and DCIS, the future holds promise in deciphering these seemingly indolent lesions.


(1.) Ewing J. Neoplastic Diseases: A Textbook on Tumors. Philadelphia, PA: WB Saunders; 1919.

(2.) Foote FW Jr, Stewart FW. Lobular carcinoma in situ: a rare form of mammary carcinoma. Am J Pathol. 1941;17:491-499.

(3.) Haagensen CD, Lane N, Lattes R, Bodian C. Lobular neoplasia (so-called lobular carcinoma in situ) of the breast. Cancer. 1978;42:737-769.

(4.) Page DL, Dupont WD, Rogers LW, Rados MS. Atypical hyperplastic lesions of the female breast: a long-term follow-up study. Cancer. 1985;55:2698-2708.

(5.) Page DL, Kidd TE Jr, Dupont WD, Simpson JF, Rogers LW. Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease. Hum Pathol. 1991;22:1232-1239.

(6.) Page DL, Schuyler PA, Dupont WD, Jensen RA, Plummer WD Jr, Simpson JF. Atypical lobular hyperplasia as a unilateral predictor of breast cancer risk: a retrospective cohort study. Lancet. 2003;361:125-129.

(7.) Lu YJ, Osin P, Lakhani SR, Di Palma S, Gusterson BA, Shipley JM. Comparative genomic hybridization analysis of lobular carcinoma in situ and atypical lobular hyperplasia and potential roles for gains and losses of genetic material in breast neoplasia. Cancer Res. 1998;58:4721-4727.

(8.) Hwang ES, Nyante SJ, Yi Chen Y, et al. Clonality of lobular carcinoma in situ and synchronous invasive lobular carcinoma. Cancer. 2004;100:2562-2572.

(9.) Page DL, Dupont WD, Rogers LW. Ductal involvement by cells of atypical lobular hyperplasia in the breast: a long-term follow-up study of cancer risk. Hum Pathol. 1988;19:201-207.

(10.) Haagensen CD, ed. Diseases of the Breast. Philadelphia, PA: WB Saunders; 1971.

(11.) Wheeler JE, Enterline HT, Roseman JM, et al. Lobular carcinoma in situ of the breast: long-term follow-up. Cancer. 1974;34:554-563.

(12.) Mastracci TL, Boulos FI, Andrulis IL, Lam WL. Genomics and premalignant breast lesions: clues to the development and progression of lobular breast cancer. Breast Cancer Res. 2007;9:215.

(13.) Eusebi V, Magalhaes F, Azzopardi JG. Pleomorphic lobular carcinoma of the breast: an aggressive tumor showing apocrine differentiation. Hum Pathol. 1992;23:655-662.

(14.) Sneige N, Wang J, Baker BA, Krishnamurthy S, Middleton LP. Clinical, histopathologic, and biologic features of pleomorphic lobular (ductal-lobular) carcinoma in situ of the breast: a report of 24 cases. Mod Pathol. 2002;15:1044-1050.

(15.) Elston CW, Ellis IO. Pathological prognostic factors in breast cancer: the value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19:403-410.

(16.) Fadare O, Dadmanesh F, Alvarado-Cabrero I, et al. Lobular intraepithelial neoplasia [lobular carcinoma in situ] with comedo-type necrosis: a clinicopathologic study of 18 cases. Am J Surg Pathol. 2006;30:1445-1453.

(17.) Simpson PT, Reis-Filho JS, Lambros MB, et al. Molecular profiling pleomorphic lobular carcinomas of the breast: evidence for a common molecular genetic pathway with classic lobular carcinomas. J Pathol. 2008;215:231-244.

(18.) Reis-Filho JS, Simpson PT, Jones C, et al. Pleomorphic lobular carcinoma of the breast: role of comprehensive molecular pathology in characterization of an entity. J Pathol. 2005;207:1-13.

(19.) Acs G, Lawton TJ, Rebbeck TR, LiVolsi VA, Zhang PJ. Differential expression of E-cadherin in lobular and ductal neoplasms of the breast and its biologic and diagnostic implications. Am J Clin Pathol. 2001;1 15:85-98.

(20.) Goldstein NS, Bassi D, Watts JC, Layfield LJ, Yaziji H, Gown AM. E-cadherin reactivity of 95 noninvasive ductal and lobular lesions of the breast: implications for the interpretation of problematic lesions. Am J Clin Pathol. 2001;115:534-542.

(21.) Jacobs TW, Pliss N, Kouria G, Schnitt SJ. Carcinomas in situ of the breast with indeterminate features: role of E-cadherin staining in categorization. Am J Surg Pathol. 2001;25:229-236.

(22.) Berx G, Cleton-Jansen AM, Nollet F, et al. E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO J. 1995;14: 6107-6115.

(23.) Berx G, Cleton-Jansen AM, Strumane K, et al. E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene. 1996;13:1919-1925.

(24.) Goldstein NS, Kestin LL, Vicini FA. Clinicopathologic implications of E-cadherin reactivity in patients with lobular carcinoma in situ of the breast. Cancer. 2001;92:738-747.

(25.) Gupta SK, Douglas-Jones AG, Jasani B, Morgan JM, Pignatelli M, Mansel RE. E-cadherin (E-cad) expression in duct carcinoma in situ (DCIS) of the breast. Virchows Arch. 1997;430:23-28.

(26.) Rieger-Christ KM, Pezza JA, Dugan JM, Braasch JW, Hughes KS, Summerhayes IC. Disparate E-cadherin mutations in LCIS and associated invasive breast carcinomas. Mol Pathol. 2001;54:91-97.

(27.) Da Silva L, Parry S, Reid L, et al. Aberrant expression of E-cadherin in lobular carcinomas of the breast. Am J Surg Pathol. 2008;32:773-783.

(28.) Aghib DF, McCrea PD. The E-cadherin complex contains the src substrate p120. Exp Cell Res. 1995;218:359-369.

(29.) Aberle H, Schwartz H, Kemler R. Cadherin-catenin complex: protein interactions and their implications for cadherin function. J Cell Biochem. 1996;61:514-523.

(30.) Piepenhagen PA, Nelson WJ. Defining E-cadherin-associated protein complexes in epithelial cells: plakoglobin, beta- and gamma-catenin are distinct components. J Cell Sci. 1993;104(pt 3):751-762.

(31.) Reynolds AB, Daniel J, McCrea PD, Wheelock MJ, Wu J, Zhang Z. Identification of a new catenin: the tyrosine kinase substrate p120cas associates with E-cadherin complexes. Mol Cell Biol. 1994;14:8333-8342.

(32.) Yap AS, Niessen CM, Gumbiner BM. The juxtamembrane region of the cadherin cytoplasmic tail supports lateral clustering, adhesive strengthening, and interaction with p120ctn. J Cell Biol. 1998;141:779-789.

(33.) Noren NK, Liu BP, Burridge K, Kreft B. p120 catenin regulates the actin cytoskeleton via Rho family GTPases. J Cell Biol. 2000;150:567-580.

(34.) Bratthauer GL, Moinfar F, Stamatakos MD, et al. Combined E-cadherin and high molecular weight cytokeratin immunoprofile differentiates lobular, ductal, and hybrid mammary intraepithelial neoplasias. Hum Pathol. 2002;33:620-627.

(35.) Bratthauer GL, Miettinen M, Tavassoli FA. Cytokeratin immunoreactivity in lobular intraepithelial neoplasia. J Histochem Cytochem. 2003;51:1527-1531.

(36.) Dabbs DJ, Bhargava R, Chivukula M. Lobular versus ductal breast neoplasms: the diagnostic utility ofp120 catenin. Am J Surg Pathol. 2007;31:427-437.

(37.) Middleton LP, Grant S, Stephens T, Stelling CB, Sneige N, Sahin AA. Lobular carcinoma in situ diagnosed by core needle biopsy: when should it be excised? Mod Pathol. 2003;16:120-129.

(38.) Crisi GM, Mandavilli S, Cronin E, Ricci A Jr. Invasive mammary carcinoma after immediate and short-term follow-up for lobular neoplasia on core biopsy. Am J Surg Pathol. 2003;27:325-333.

(39.) Shin SJ, Rosen PP. Excisional biopsy should be performed if lobular carcinoma in situ is seen on needle core biopsy. Arch Pathol Lab Med. 2002;126:697-701.

(40.) Arpino G, Allred DC, Mohsin SK, Weiss HL, Conrow D, Elledge RM. Lobular neoplasia on core-needle biopsy-clinical significance. Cancer. 2004;101:242-250.

(41.) Elsheikh TM, Silverman JF. Follow-up surgical excision is indicated when breast core needle biopsies show atypical lobular hyperplasia or lobular carcinoma in situ: a correlative study of 33 patients with review of the literature. Am J Surg Pathol. 2005;29:534-543.

(42.) Karabakhtsian RG, Johnson R, Sumkin J, Dabbs DJ. The clinical significance of lobular neoplasia on breast core biopsy. Am J Surg Pathol. 2007;31:717-723.

(43.) Nagi CS, O'Donnell JE, Tismenetsky M, Bleiweiss IJ, Jaffer SM. Lobular neoplasia on core needle biopsy does not require excision. Cancer. 2008;112: 2152-2158.

(44.) Menon S, Porter GJ, Evans AJ, et al. The significance of lobular neoplasia on needle core biopsy of the breast. Virchows Arch. 2008;452:473-479.

(45.) 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;21:1208-1216.

(46.) Port ER, Park A, Borgen PI, Morris E, Montgomery LL. Results of MRI screening for breast cancer in high-risk patients with LCIS and atypical hyperplasia. Ann Surg Oncol. 2007;14:1051-1057.

(47.) Debnath J, Walker SJ, Brugge JS. Akt activation disrupts mammary acinar architecture and enhances proliferation in an mTOR-dependent manner. J Cell Biol. 2003;163:315-326.

(48.) Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004;165:263-273.

(49.) Derksen PW, Liu X, Saridin F, et al. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell. 2006;10:437-449.

(50.) Green AR, Krivinskas S, Young P, et al. Loss of expression of chromosome 16q genes DPEP1 and CTCF in lobular carcinoma in situ of the breast. Breast Cancer Res Treat. 2008;113:59-66.

Alejandro Contreras, MD, PhD; Husain Sattar, MD

Accepted for publication February 5, 2009.

From the Department of Pathology, University of Chicago, Chicago, Illinois.

Presented in part at the Current Issues in Diagnostic Pathology conference, University of Chicago, Chicago, Illinois, October 2008.

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

Reprints: Husain Sattar, MD, Department of Pathology, University of Chicago, MC6101, 5841 S Maryland Ave, Chicago, IL 60637 (e-mail: husain.sattar@uchospitals.edu).
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