LCIS is most frequently diagnosed in women aged 40 to 55 years (4, 11). The true prevalence of LCIS in the general population, however, is difficult to estimate and likely exceeds the incidence, given that it does not present as a mass lesion nor does it have a specific radiographic appearance. Lesions diagnosed in the pre-mammography screening era were typically incidental microscopic findings in biopsies and excision specimens obtained for other reasons (2, 4). The reported incidence of LCIS in otherwise benign breast biopsy specimens ranges from 0.5% to 3.8% (4, 11), whereas population-based data reported to Surveillance, Epidemiology, and End Results (SEER) from 1978 to 1998 demonstrate an incidence of 3.19 per 100,000 women (12). It is noteworthy, however, that during this time period there was an observed four-fold increase in the number of LCIS cases reported among women over 40 years of age, with the highest incidence rate (11.47 per 100,000 person-years) in 1998 among women 50 to 59 years of age. While this trend may reflect the increasing use of mammography and image-guided biopsies during this time period (12, 13), the impact of other factors, such as the use of postmenopausal hormone replacement and more accurate pathologic diagnosis of LN based on ancillary immunohistochemical markers (see below) remains a matter of speculation. LCIS is often multifocal, with more than 50% of patients diagnosed with LCIS showing multiple foci in the ipsilateral breast. Furthermore, bilateral lesions are reported in approximately one-third of patients (14, 15). Such multifocality in a clinically non-detectable lesion is one of the reasons why planning subsequent management has proven problematic and contentious. More recent imaging series suggest that LCIS may be associated with microcalcifications (16), and LCIS has been reported to enhance on MRI (17); however, imaging criteria to differentiate LCIS from overt malignancy are lacking, and, as such, women with LCIS are frequently subject to multiple biopsies demonstrating otherwise benign findings.

The clinical characteristics of LCIS, including its multifocal and bilateral distribution, and evidence of familial clustering (18, 19) have led to the hypothesis that these lesions could be underpinned by germline genetic abnormalities. Although a hereditary form of diffuse gastric cancer and breast lobular carcinoma caused by CDH1 germline mutations (20) has been described, the potential genes involved and the pattern of inheritance of familial LCIS outside of this context remain unclear (see below).

The clinical characteristics of LCIS that support its role as a risk factor for the subsequent development of breast cancer include the cumulative long-term risk of breast cancer development that is generally conferred to both breasts, averaging 1% to 2% per year, and the observation that not all breast cancers developing after a diagnosis of LCIS are of lobular histology (reviewed in reference (21). The incidence of invasive breast cancer following a diagnosis of LCIS is steady over time (22), with a similar number of invasive lesions being reported within and after 5 years of follow-up (23). Others have also demonstrated the cumulative long-term risk, with one study reporting that over 50% of patients developed beast cancer between 15 and 30 years of follow-up (5). ALH is also associated with an increased risk of subsequent breast cancer; however, this is of a lower magnitude than that conferred by LCIS. Patients diagnosed with ALH have a four- to five-fold higher risk than the general population (i.e., women of comparable age who have had a breast biopsy performed with no atypical proliferative disease diagnosed), whereas a relative risk of 8 to 10 times is conferred by a diagnosis of LCIS (11, 24, 25). Hence, these observations suggest that the term LN, albeit helpful to describe this group of lesions collectively, may not suffice to guide the management of patients with lobular lesions, and specific classification of LN into ALH and LCIS may still be justified. It should be noted, however, that the distinctions between ALH and LCIS are subjective and, for some experts, the differences between these two categories of LN are more easily expressed in words than in actual practice (23).

The risk of breast cancer development following a diagnosis of ALH or LCIS is bilateral (14, 22, 26), which is consistent with the notion that these lesions are risk indicators; however, some have reported a higher rate of breast cancer in the ipsilateral breast (9, 21, 27), supporting a precursor role for LCIS. The histological type of breast cancer following a diagnosis of LN also differs among these reports. In studies that suggest the risk is conferred equally to both breasts, there are, similarly, an equal number of subsequent IDCs and ILCs reported to occur after a diagnosis of LCIS (22), which is consistent with the notion that LCIS would not constitute a true precursor lesion. On the other hand, in most studies that report a higher incidence of ipsilateral cancer development, the majority of the cancers are of lobular histology (8, 21, 23). This clinical observation, in parallel with SEER data demonstrating an increasing incidence of both LCIS and ILC from the late-1980s to the mid-1990s among women 50 years of age and older (12, 28), have led to renewed interest the debate over the clinical significance of LCIS.

Taken together, the current epidemiological, observational, and clinical data support the contention that LN is not only a risk indicator, but also a non-obligate precursor of invasive breast cancer. This notion is lent further credence by the striking morphologic similarities between cells of ALH or LCIS and ILC, and molecular data demonstrating the clonality between LN and synchronous invasive breast cancer (see below); in particular, the presence of concordant gene copy number and allelic abnormalities (6, 29), mitochondrial DNA mutations (7), and identical CDH1 gene mutations in matched LCIS and ILC from the same patients (10).

Despite the controversies surrounding the clinical implications of ALH and LCIS, their histologic features have been well characterized. The latest World Health Organization (WHO) classification of breast tumors defines LN as “a spectrum of atypical epithelial lesions originating in the terminal ductlobular unit and characterized by a proliferation of generally small, non-cohesive cells, with or without pagetoid involvement of the terminal ducts” (30). At scanning magnification, these lesions are characterized by a variable enlargement of the acini, which are filled up and, at least in part, are expanded by a proliferation of monomorphic population of dyshesive
small, round, or polygonal cells, with inconspicuous cytoplasm (Fig. 22-1). In fact, the main histological characteristic of LN is that its cells are loosely cohesive, regularly spaced, and fill and distend the acini, with an overall maintenance of the lobular architecture (Fig. 22-2). Intracytoplasmic vacuoles, sometimes containing a central eosinophilic dot (known as magenta body), are usually found (2, 4, 21, 30). Despite the apparent monomorphism of the classic variant of LN, some variability in the cytomorphology between different cases, and frequently within the same case, is easily appreciated, and two cytologic subtypes have been recognized (Table 22-1). Type A cells are small, dyshesive cells with scant cytoplasm and nuclei approximately 1.5 times the size of that of a lymphocyte, whereas type B cells have more abundant, often clear cytoplasm nuclei that are approximately two times bigger than a lymphocyte nucleus, mild-to-moderate nuclear atypia (nuclear pleomorphism 1 or 2), and indistinct or absent nucleoli (21, 31). It should be noted, however, that this cytological classification scheme has not been shown to be of clinical utility and does not have a direct correlation with the risk of invasive breast cancer development. Other than an academic exercise, this classification system is only a reminder that some degree of cytologic variation can be observed in bona fide cases of classic LN. In the classic form of LN, mitoses and necrosis are uncommon. Pagetoid spread within the affected terminal duct-lobular unit, whereby the neoplastic cells extend along adjacent ducts between intact overlying epithelium and underlying basement membrane, is frequently observed (Fig. 22-3). The presence of glandular lumina is not seen in fully developed cases; it should be noted, however, that in lobules partially affected by LN, residual glandular structures can be found.

The sub-classification of LN into ALH and LCIS is quantitative rather than qualitative (30). While for a diagnosis of LCIS more than half the acini in an involved lobular unit must be filled and distended by the characteristic cells, leaving no central lumina, ALH is defined as a less well-developed and less-extensive lesion, where the characteristic cells only partly fill the acini, with only minimal or no distention of the lobule (Fig. 22-4), and glandular lumina can still be found (9, 24, 30, 32). In an attempt to standardize the diagnosis of ALH and LCIS, it has been proposed that lobular distention should be defined as eight or more cells present in the crosssectional diameter of an acinus, and that the number of acini involved in cases of ALH should account for less than half of the whole terminal duct-lobular unit (9, 24, 30, 32). Although the use of this sub-classification would be justified on the basis of the lower risk conferred by ALH than by LCIS, the differentiation between ALH and LCIS based on the criteria described above is not only arbitrary, but also subjective, prone to interobserver and intraobserver variability, and dependent on the extent of sampling of a given lesion. Therefore, the use of the term LN to encompass the whole range of changes, and remove this variability, is preferable for diagnostic purposes, particularly in core needle biopsy specimens (21, 33). In fact, in the context of diagnostic core biopsies, the term LN, with no attempt to distinguish ALH and LCIS, is recommended in the guidelines of breast cancer screening programs (e.g., the United Kingdom National Health Service Breast Screening Programme [NHS BSP]) (33).

Arguably, a more relevant distinction is between the classic form of LN and the pleomorphic variant of LCIS (PLCIS), which was first identified as a distinct entity by Eusebi et al. in 1992 (34). This variant is characterized by pleomorphic cells that are substantially bigger than those of classic LN (31, 34), and by more abundant, pink, and often finely granular cytoplasm. Features of apocrine differentiation are frequently found (34, 35). As compared to the nuclei of classic LN, PLCIS nuclei are bigger (four times the size of lymphocyte nucleus), more pleomorphic, and atypical nuclei, often containing conspicuous nucleoli (Fig. 22-5). PLCIS not uncommonly presents with central, comedo-type necrosis and microcalcifications; yet, necrosis is not required for the diagnosis. Recognition of the pleomorphic subtype is important because the combination of cellular features, necrosis, and calcification can lead to difficulty in differentiation from DCIS, and potentially overtreatment, although data regarding the natural history of PLCIS are very limited. Until additional data regarding the natural history of PLCIS are available, this distinction has important implications for treatment. Whereas some advocate for a more aggressive approach to PLCIS, with treatment recommendation akin to those for DCIS, it should be noted that this approach is supported
only by molecular data demonstrating that PLCIS shares many similarities with pleomorphic ILC, not by long-term outcomes data.

Additional variants of LN have been reported, including apocrine, histiocytoid, rhabdoid, endocrine, amphicrine, and the apocrine PLCIS variant (21, 30). The biological and clinical significance of these lesions also remains to be determined.

A further system for classification of LN has been proposed using the terminology lobular intraepithelial neoplasia (LIN), with subdivision, based on morphologic criteria and clinical outcome, into three grades (LIN 1, LIN 2, LIN 3), with LIN 3 representing the PLCIS end of the spectrum (36, 37). This system pre-supposes that the risk of invasive carcinoma development would be related to increasing grade of LIN. This classification system, albeit interesting and potentially sparing women from a diagnosis of “carcinoma” in the case of LCIS, is supported by limited evidence and has not been endorsed in the latest edition of the WHO classification (30).