The postnatal development of the mammary gland is a very complicated process orchestrated mainly by the concerted efforts of systemic steroids, peptide hormones, as well as local growth factors [1–3]. In the process which can span up to 50 years, the gland goes through four tightly regulated stages: ductal morphogenesis, lobuloalveolar development during pregnancy, synthesis and secretion of milk proteins and lipids at lactation, and involution following weaning. In addition, the ductal and lobular structures also undergo cyclic changes (proliferation and apoptosis) corresponding to the menstrual phases. Derived from the terminal end buds (TEB), the adult mammary functional and histological unit, terminal duct lobular unit (TDLU), is the site where most breast lesions arise. Upon close review of the TDLU, one could discern three distinct parts of the unit with each of them having their corresponding benign and neoplastic simulators (Fig. 10.1).

The ductal part:

The lobular (acinar) part:

The junction part:

In breast pathology, the designations “lobular,” “ductal,” and “tubular” only denote the neoplastic cell differentiation rather than the actual tumor site. Understandably, the in situ component of one type can progresses into or associate with another type of invasive carcinoma.

A well-developed myoepithelial layer lines almost the whole gland system except for a short segment of the collecting duct at the nipple orifice. This layer plays a very important chaperone role in the organogenesis and functions of the gland (see more discussion in the invasive carcinoma section).

The concept of low-grade breast neoplasia family has gained increasing recognition in recent years. Included in this family are low-grade ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), columnar cell lesion (CCL), flat epithelial atypia (FEA), and low-grade invasive carcinoma. This family shares characteristic deletion of 16q and gains of 1q and 16p [4–6]. The preinvasive lesions in this family are characterized by two morphological features: a bland and monomorphic cell population and presence of a peripheral myoepithelial layer. Compared to benign proliferative lesions (ductal hyperplasia in particular), the neoplastic precursor cells are actually more mature and differentiated toward luminal cells probably as a result of increased proliferation of estrogen receptor (ER) expressing cells which rely on autocrine growth factors.

The low-grade precursor lesions are clonal proliferations of apparent luminal cells or transit amplifying cells in which the differentiation switch toward myoepithelial is inactivated [7, 8]. This clonal proliferation of mildly defective cells accounts for the cellular monotony and blandness of low-grade precursor lesions. This cellular feature tends to get neglected if the stereotypic picture of dysplasia (increased N/C ratio and cellular polymorphism) predominates in the mind’s eye of the pathologist. This feature is particularly important in their distinction from florid ductal hyperplasia which has many features of dysplasia. An analogy exists in lymph nodes where a low-grade B cell lymphoma contains a monomorphic cell population, whereas reactive cells are polymorphic and even alarmingly atypical.

LCIS cells have lost their adhesion molecule E-cadherin and thus are loosely cohesive, whereas the molecule expression is preserved in DCIS, CCL, and FEA accounting for their cellular cohesiveness and maybe even polarity. This important feature is often used in the distinction between pleomorphic lobular carcinoma from high-grade ductal carcinoma and in the diagnosis of cancerization of lobules by DCIS cells. In cancerization, neoplastic cells involve the lobules and replace the normal luminal cells. On the other hand, lobular carcinoma cells can involve ductules in a pagetoid spread pattern in which the neoplastic cells manage to drive a wedge between the ductular luminal and myoepithelial cells. They can even form small acinar structure along the ductal lumen (clover leaf pattern).

The myoepithelial cells present at the periphery are not part of the monoclonal proliferation. Rather they represent remnants of TDLUs which have been occupied by neoplastic cells. The clonal epithelial cells have gained the capacity to break away from the inhibitory control of myoepithelial cells but are still restricted by the barrier composed of myoepithelial cells and the basement membrane. Evidence is emerging that the seemingly normal myoepithelial cells are altered at least functionally [9, 10].

The overemphasis of a uniform cell population in distinction between carcinoma in situ and benign proliferation can be problematic for papillary lesions. It is known that some papillary DCISs have a dimorphic population [11–13]. The second group of cells stands out because of their abundant pale cytoplasm. Their basally located nuclei reinforce the impression that a layer of myoepithelial cells are present. Attention to other features such as thin, delicate fibrovascular core and cell polarity and judicious use of myoepithelial markers can help avoid an underdiagnosis.

When a papilloma is involved by low-grade DCIS, the myoepithelial layer within the tumor is oftentimes attenuated as in papillomas, particularly those with superimposed ductal hyperplasia. In both situations, a myoepithelial layer is still present in the peripheral ductal wall. To identify the DCIS area, attention to cellular uniformity and blandness takes precedence. The neoplastic cells can grow on the scaffold of a preexisting papilloma which might be affected by ductal hyperplasia, rendering evaluation for papillary structure and myoepithelial cell less useful. In ambiguous cases, a stain for CK5/6 stain or estrogen receptor (ER) can be used. Hyperplastic ductal cells show a typical mosaic pattern for CK5/6 which is negative for neoplastic cells. The neoplastic cells are diffusely and strongly positive for ER which shows only focal and weak positivity for hyperplastic cells.

Papillary carcinomas are frequently mistaken for papillary DCIS. They lack, however, myoepithelial cells not only at the periphery but also inside the tumor mass.

When CCL proliferation creates mounds, differentiation from micropapillary DCIS is in order even though the distinction is most likely of no diagnostic significance. CCL cells have pencillate nuclei and the micropapillae lack a club-shaped and Roman bridge-like structures characteristic of micropapillary DCIS.

The ductal hyperplasia cells can form micropapillae. They are, however, slender with neither cellular uniformity and polarity nor bridge arch structures.