and Aysegul A. Sahin2
Division of Pathology, Singapore General Hospital, Singapore, Singapore
The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA
KeywordsLobular neoplasiaAtypical lobular hyperplasiaLobular carcinoma in situPleomorphicInvasive lobular carcinomaE-cadherin
Lobular breast lesions described in this chapter encompass a spectrum of conditions that share in common a proliferation of neoplastic lobular-type cells, which are morphologically rounded, mostly uniform cells with a tendency for discohesion.
Lobular neoplasia refers to the presence of these cells within the terminal ductal lobular unit, with or without pagetoid extension along terminal and segmental ducts. Lobular neoplasia includes atypical lobular hyperplasia and lobular carcinoma in situ (LCIS), which are distinguished by the degree and extent of lesional involvement of the terminal ductal lobular unit.
Invasive lobular carcinoma comprises invading tumour cells with lobular morphology and unique patterns of infiltration.
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Lobular Neoplasia (Atypical Lobular Hyperplasia and Lobular Carcinoma In Situ)
Lobular neoplasia is a non-invasive, abnormal proliferation of discohesive cells within the lobule. Lobular neoplastic cells are characterised by aberration of the E-cadherin gene leading to a dysfunctional E-cadherin protein, an intercellular adhesion molecule. Lobular neoplasia usually features cells with uniform, rounded morphology referred to as type A cells, but it may also be composed of type B cells with moderate nuclear variation.
Clinical and Epidemiological Features
Lobular neoplasia may be encountered in up to 4 % of breast core biopsies, often in premenopausal women . As it is usually an incidental lesion discovered during histologic evaluation of biopsy specimens and excisions performed for other clinicoradiological indications, there are no specific clinical or radiological characteristics of lobular neoplasia per se. Unusually, lobular neoplasia may be mass forming, resulting in clinical or radiological detection, and occasionally it can be associated with necrosis and calcifications leading to mammographic discovery .
Most lobular neoplastic lesions do not have specific imaging features, apart from those variants that are mass forming or accompanied by calcifications. The majority are incidental findings on biopsy. Sampled microcalcifications are not commonly found within the lobular neoplasia itself, but are discovered more frequently in adjacent cystic alterations or atypical ductal hyperplasia. Lobular carcinoma in situ (LCIS) can occasionally form irregular masses and present as suspicious non-mass enhancement on MRI . Pleomorphic LCIS may display clustered, punctate, or pleomorphic-type microcalcifications on mammography .
Lobular neoplasia is usually a microscopic lesion that does not produce a macroscopic abnormality. Mass-forming examples can be associated with a grossly visible lesion (Fig. 10.1), and those harbouring calcifications can be gritty in consistency.
Florid lobular carcinoma in situ (LCIS). This skin-sparing mastectomy specimen shows multiple fleshy nodules with a pinkish-grey appearance (arrows) amid fibrofatty breast parenchyma
Both atypical lobular hyperplasia and LCIS are composed of monomorphic, discohesive, round cells in the terminal ductal lobular unit, differing by the severity of involvement of lobules. In atypical lobular hyperplasia, the neoplastic cells variably fill the acini, leading to rounded acinar contours, but they do not significantly distend or distort the acinar shapes (Figs. 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, and 10.10). In LCIS, there is filling of all acini in the affected lobule, accompanied by distention and/or distortion of at least half of the filled acini (Figs. 10.11, 10.12, 10.13, 10.14, 10.15, 10.16, 10.17, 10.18, and 10.19). Not infrequently, there is a gradation of changes, and it may be difficult to clearly separate atypical lobular hyperplasia from LCIS. There is also interobserver variability in the assessment of the degree of lobular neoplastic changes. It is useful to distinguish atypical lobular hyperplasia from LCIS because the risk implications for subsequent development of breast carcinoma differ, but to do so is admittedly challenging in some cases, whereupon lobular neoplasia may be applied as an encompassing term. Lobular neoplasia can coexist with columnar cell lesions, flat epithelial atypia, atypical ductal hyperplasia, and low-grade invasive carcinoma, referred to as the “low nuclear grade neoplasia family” of breast lesions (Figs. 10.20, 10.21, 10.22, and 10.23) .
Marked nuclear pleomorphism, often with apocrine cytomorphology, is sometimes seen in LCIS and is referred to as the pleomorphic variant (Figs. 10.24, 10.25, 10.26, 10.27, 10.28, 10.29, 10.30, 10.31, 10.32, 10.33, 10.34, and 10.35) . Necrosis and calcifications may be found in pleomorphic LCIS, but they can also be observed in classic forms of the disease. Lobular neoplasia with type B cells should not be diagnosed as pleomorphic LCIS. When required, E-cadherin immunohistochemistry can be used to confirm a lobular phenotype, displaying negative staining of the lobular neoplastic cells . It is important to be familiar with aberrant E-cadherin staining patterns (Figs. 10.36, 10.37, and 10.38) . Other immunohistochemical markers include p120 catenin and β-catenin, which show cytoplasmic rather than membrane localisation of staining .
Atypical lobular hyperplasia. At low magnification, the terminal ductal lobular units contain monomorphic, discohesive cells. The luminal spaces of terminal ducts and acini are obscured
Atypical lobular hyperplasia. High magnification shows the discohesive cells filling the acinar spaces. No distension or distortion of the acinar outlines is seen
Atypical lobular hyperplasia shows a monomorphic, discohesive epithelial population filling the acini. The cells display inconspicuous spaces in between them, with ill-defined cell contours and cytoplasmic membranes. The epithelial lining of the terminal duct is attenuated. These lobular neoplastic cells are of type A morphology
Atypical lobular hyperplasia. Lobular neoplastic cells show a greater degree of nuclear variation, with several slightly enlarged, vesicular nuclei and discernible nucleoli; features are consistent with type B cells. Occasional cytoplasmic vacuoles are seen
Atypical lobular hyperplasia shows cells with cytoplasmic vacuoles and discohesion, filling but not distending acinar spaces of the lobule. Affected acini show rounded contours
Atypical lobular hyperplasia is seen adjacent to an unaffected terminal duct, with atypical lobular neoplastic cells filling the affected terminal duct and acini
Atypical lobular hyperplasia. E-cadherin immunohistochemistry shows diminished and absent staining in the lobular neoplastic cells. There appears to be some patchy E-cadherin staining in affected ducts and acini, which may reflect staining of intermingled myoepithelial cells. Some lobular neoplastic cells can also demonstrate diminished and incomplete E-cadherin staining of their cytoplasmic membranes
Atypical lobular hyperplasia. E-cadherin immunostaining shows positive cytoplasmic membrane reactivity of the epithelial cells lining the terminal duct, whereas the lobular neoplastic cells are devoid of E-cadherin expression, apart from some staining likely originating from intermingled myoepithelial cells
Lobular neoplasia (atypical lobular hyperplasia) featuring a histiocytoid appearance
Lobular carcinoma in situ (LCIS) with pagetoid extension along the terminal duct. Lobular neoplastic cells insinuate in between the luminal epithelium and the myoepithelial cells. Pagetoid extension may be encountered in both atypical lobular hyperplasia and LCIS. Adjacent acini are distended by lobular neoplastic cells with distortion of their outlines, features of LCIS
Lobular neoplasia with pagetoid extension. E-cadherin immunohistochemistry shows preserved staining in luminal epithelial cells; the lobular neoplastic cells are negative. It is difficult to be certain from this illustration whether the lesion represents atypical lobular hyperplasia or LCIS; a final conclusion will depend on assessing the entire lesion especially the severity of changes in the acini
E-cadherin immunohistochemistry shows negative staining of LCIS cells, whereas there is positive staining for attenuated luminal epithelial cells, as well as the peripheral myoepithelial cells
Lobular carcinoma in situ. Duct and acinar spaces are completely filled and distended by lobular neoplastic cells. When assessing whether there is distension of acini, comparison with adjacent uninvolved lobules is useful
Lobular carcinoma in situ. At low magnification, LCIS shows discohesive cells with pink cytoplasm suggesting an apocrine cytomorphology. Several unaffected acini are seen; when compared with acini involved by lobular neoplasia, there is confirmation of acinar distension by lobular neoplastic cells
Lobular carcinoma in situ with apocrine pleomorphic features. Here, the nuclei show moderate and marked pleomorphism, with pink cytoplasm indicating apocrine cytomorphology. A mitosis is seen (white arrow)
Lobular carcinoma in situ. Fractured calcifications are observed in several distended islands of LCIS. Inset shows negative E-cadherin staining of LCIS cells
Lobular carcinoma in situ with apocrine features. Apocrine cells with characteristic pink cytoplasm and enlarged vesicular nuclei with discernible nucleoli distend the duct spaces. The cells show discohesion
Lobular carcinoma in situ with apocrine features. E-cadherin immunohistochemistry shows negative staining of the lobular neoplastic cells. A few individual cells in several affected spaces disclose incomplete cytoplasmic membrane staining
Lobular neoplasia associated with calcifications. Infrequently, lobular neoplasia may be accompanied by calcifications, which can be detected mammographically. More often, lobular neoplasia is incidentally identified adjacent to columnar cell lesions that calcify, rather than being directly associated with calcifications
Lobular carcinoma in situ (arrow) with adjacent columnar cell hyperplasia and calcifications
Lobular carcinoma in situ with invasive tubular carcinoma. Low magnification of breast tissue shows LCIS affecting multiple terminal ductal lobular units. Centrally, there is an invasive tubular carcinoma composed of haphazardly placed tubules. Invasive lobular carcinoma is also present (arrow) but is difficult to appreciate at this low magnification
Lobular carcinoma in situ with invasive tubular carcinoma. Patent, rounded, and angulated tubules of invasive tubular carcinoma are found adjacent to LCIS. Lobular neoplasia, flat epithelial atypia, atypical ductal hyperplasia, and low-grade invasive carcinomas form part of the spectrum of the low nuclear grade neoplasia family of breast lesions
Pleomorphic LCIS. This duct space is expanded by abnormal, discohesive cells with moderate to marked nuclear pleomorphism. Some cells show cytoplasmic vacuoles. Cytoplasm of many cells is pink, giving an apocrine appearance. A calcification is noted. The diagnosis of pleomorphic LCIS requires the presence of marked nuclear pleomorphism (grade 3 nuclei)
Pleomorphic LCIS. Immunohistochemistry for p120 catenin shows cytoplasmic localisation of staining, without any membrane reactivity. In interpreting p120 catenin staining, it is important to compare with the internal positive controls of benign ducts and ductules, which display crisp membrane positivity, in contrast to the cytoplasmic reactivity of lobular neoplasia and invasive lobular carcinoma. Sometimes, apposition or overlapping of lobular neoplastic and lobular carcinoma cells can lead to an accentuation of staining near the cytoplasmic membrane, which may mimic membrane staining (Reprinted from Ho and Tan ; with permission)
Lobular carcinoma in situ within a radial sclerosing lesion. Excision of a radiologically stellate lesion shows an ill-defined, whitish, firm area in the breast tissue (arrow). Histological assessment disclosed a radial sclerosing lesion with superimposed LCIS
Lobular carcinoma in situ within a radial sclerosing lesion. At scanning magnification, the fibrotic core of the radial sclerosing lesion is seen (arrow). Solidified epithelial islands radiate from the fibrotic centre
Lobular carcinoma in situ within a radial sclerosing lesion. At low magnification, there is a central fibrotic nidus around which the solidified duct spaces emanate
Lobular carcinoma in situ within a radial sclerosing lesion. A discohesive cell population fills the duct and acinar spaces. The largest duct space is distended by pleomorphic apocrine cells with intercellular spaces and apoptosis, features of pleomorphic apocrine LCIS. Surrounding acini contain a more uniform population of classic LCIS, accompanied by a calcification (left field)
Lobular carcinoma in situ with pleomorphic apocrine features. Occasional intracytoplasmic lumens are present (black arrows), with a targetoid secretory droplet observed in one lumen (white arrow)
Pleomorphic apocrine LCIS. Discohesive apocrine cells with moderate to marked nuclear pleomorphism and pink cytoplasm distend duct spaces
Pleomorphic apocrine LCIS. Multinucleation (arrows) and intranuclear inclusions are present
Lobular carcinoma in situ within a radial sclerosing lesion. E-cadherin immunohistochemistry shows loss of staining in the lobular neoplastic cells
Lobular carcinoma in situ within a radial sclerosing lesion. Higher magnification shows negative staining for E-cadherin in the lobular neoplastic cells, with a positively stained peripheral myoepithelial rim
Pleomorphic apocrine LCIS shows positive staining for c-erbB-2 (HER2). This type of staining is not performed for prognostic purposes, but it can be applied to support a pleomorphic morphology, as pleomorphic LCIS has a higher rate of c-erbB-2 overexpression
Aberrant E-cadherin staining in LCIS shows cytoplasmic rather than membrane staining, contrasting against the membrane localisation of E-cadherin in the adjacent ducts
Aberrant E-cadherin staining. (a) Invasive lobular carcinoma cells show diminished intensity and incomplete membrane staining for E-cadherin, contrasting against the benign ducts and acini, which disclose more intense membrane reactivity of epithelial cells. (b) A globular, dot-like staining is seen in the cytoplasm of invasive lobular carcinoma cells. Inset shows paranuclear globular staining for E-cadherin of lobular carcinoma cells
(a) Lobular neoplasia comprising both atypical lobular hyperplasia and lobular carcinoma in situ is present in the breast tissue (left), confirmed with E-cadherin immunohistochemistry that reveals diminished staining in several of the affected acini. Some of the acini that are affected by lobular neoplasia however, appear to retain E-cadherin staining at this magnification. (b) Higher magnification of several acini affected by lobular neoplasia, with rounded discohesive cells with occasional intracytoplasmic lumens. A small acinar lumen is discerned (arrow). (c) Immunohistochemistry of apparently positive E-cadherin membrane staining in acini that on light microscopy showed involvement by lobular neoplasia. Close scrutiny shows epithelial cells lining the central lumens of the acini to disclose smooth continuous linear staining of their cytoplasmic membranes (black arrows), while the surrounding cells display thick clumpy membrane positivity (red arrows), which may be interpreted as aberrant staining. (d) Closer view of E-cadherin immunostaining shows thick, clumpy and smudgy cytoplasmic membrane staining of lobular neoplastic cells, compared against the smooth, uninterrupted and continuous cytoplasmic membrane staining of luminal epithelial cells
Myoepithelial Hyperplasia and Apocrine Cells
Myoepithelial hyperplasia may resemble lobular neoplasia when the hyperplastic myoepithelial cells encroach against and obscure luminal epithelial cells (Figs. 10.39 and 10.40). These myoepithelial cells may display pale to clear cytoplasm with round nuclei that mimic lobular neoplasia. Lobular neoplasia is often multifocal, whereas myoepithelial hyperplasia may be confined to specific acini within a lobule, and cellular discohesion is not a distinct feature. Immunohistochemistry for E-cadherin is helpful in verifying its membranous retention in myoepithelial hyperplasia, although the staining in myoepithelial cells may be slightly less intense than in the luminal epithelial cells. Occasionally, apocrine cells in acini can also mimic lobular neoplastic cells (Figs. 10.41, 10.42, 10.43, and 10.44).
Myoepithelial hyperplasia. Prominence of myoepithelial cells at the periphery of ducts and acini may resemble lobular neoplasia. In contrast to lobular neoplasia, myoepithelial hyperplasia is seen as a layer of cells at the periphery, without substantial effacement of the luminal epithelial population
Myoepithelial hyperplasia. Prominent myoepithelial cells are seen rimming the luminal epithelial cells. There is no effacement of the luminal spaces, nor rounded contouring of acini
Apocrine cells in acini resembling lobular neoplasia. In a few acini of this lobule, there are scattered rounded, plump cells with pale to light pink cytoplasm and central vesicular nuclei, interspersed among the luminal epithelial cells and myoepithelial cells, mimicking atypical lobular hyperplasia
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