Benign Breast Lesions

The normal breast is made up of lobules and ducts (Slide 1). Both are lined by two layers of cells: inner secretory epithelial cells and outer myoepithelial cells (Slide 2).

Epithelial cells have columnar or cuboidal shape and their amount of cytoplasm depends on the hormonal influence. Under active hormonal stimulation, the cells maintain tall shape and abundant cytoplasm. Cuboidal configuration and decreased cytoplasm characterize inactive hormonal influence.

Myoepithelial cells are located beneath the epithelial cells and have smaller, darker nuclei, which are elongated when cut longitudinal and triangular in cross sections. In longitudinal sections, myoepithelial cells have fibrillar eosinophilic cytoplasm, due to the presence of smooth muscle contractile protein, which provides contractility to squeeze the duct and to push the secretory product towards the nipple. Myoepithelial cells can be identified by immunohistochemical stains for S-100 protein and smooth muscle actin (Slide 3).

I. FIBROCYSTIC CHANGE

 

Fibrocystic "disease" or change is one of the most common benign conditions that affects more than 50 percent of women having palpably irregular breasts, cyclic pain, and tenderness. It is related to regular and, sometimes irregular, menstrual cycles with hormonal fluctuations. The target organ, mammary tissue, in response to the imbalanced estrogen and progesterone stimulation over time, undergoes a wide variety of morphologic changes under the old term of fibrocystic change. Essentially, at the time of increased estrogenic stimulation epithelial cells proliferate in the ducts (ductal hyperplasia) and lobules (adenosis). With decreased estrogen levels, the epithelium involutes, the ducts become cystic, and the lobules and stroma increase fibrous tissue (sclerosing adenosis and stromal fibrosis, respectively).

Thus, fibrocystic change occurs in the following three major elements through the mediation of estrogen and progesterone receptors:

1. ducts: ductal hyperplasia and cyst formation

2. lobules: adenosis (lobular hyperplasia) and sclerosing adenosis

3. stroma: fibrosis

A lack of uniform criteria for the term of "fibrocystic change" for many years created controversies as to the relationship to breast cancer. The original study by Dupont and Page (1985) has demonstrated the importance of precisely classifying and specifying epithelial proliferations into those with and without atypia. Based on the review of more than 10,500 consecutive benign breast biopsies for benign diseases from 3,300 women who were followed for a median period of 17 years, the relative risk of specific changes is summarized as follows:

How to translate the relative risk factors to prevalence rates? During a 15-year follow-up period, 20% of women who have atypical hyperplasia and a family history of breast cancer developed breast cancer, as compared to 8% for those with atypical hyperplasia and without family history. The comparable rates are 2% for women without non-proliferative change and 4% with proliferative change without atypia.

In the subsequent studies by Dupont and Page (1986 and 1989), the highest risk for the development of invasive breast carcinoma occurs during the first 10 years after biopsy and the risk decreases thereafter. This implies that the most critical follow-up should be the initial 10 years following diagnosis.

 

The importance of atypical hyperplasia as a biologic marker for increased risk of developing invasive breast cancer has been confirmed in a multicenter study involving more than 280,000 women (Dupont et al, 1993). For these reasons, the morphologic criteria and definition as proposed by Dupont and Page are adopted in this presentation. Needless to say, these changes should be recognized and reported in the pathology reports.

A. Cysts

Cysts are fluid-filled spaces that originate from the terminal ductal lobular unit or from an obstructed ectatic duct. They are frequently multiple and bilateral and may vary in size from microscopic to a few centimeters. Cysts are the most common breast masses in women aged 40 to 50 years (Bassett et al).

The cysts are usually multiple and measure in size from 2 mm to greater than one cm (Slides 4 and 5). They are lined attenuated, atrophic ductal cells (Slide 6) or apocrine metaplastic cells (Slide 7). The apocrine cells have abundant eosinophilic, granular cytoplasm and cytoplasmic protrusions into the luminal border, so called apocrine snouts (Slide 8). The nuclei often prominent nucleoli. It is common to find papillary projections (Slide 9).

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B. Epithelial Hyperplasia With and Without Atypia

Epithelial hyperplasia is divided into ductal and lobular types under the low power microscopic observation. In general, lobules include acini and terminal ductules, whereas ducts comprise of interlobular ducts and beyond. It should be emphasized that, due to the substantial individual variations under the influence of hormones, the separation between lobules and ducts is subjective and sometimes arbitrary.

The "usual" ductal hyperplasia The morphologic hallmarks of ductal hyperplasia is increased cellularity and altered architectures, most commonly with

1. papillary formation (Slide 10)

2. sieve-like, cribriform, back to back pattern (Slide 11)

3. solid filling of ductal lumens (Slide 10)

These ductal hyperplasias have also been referred to by various authors as epitheliosis and papillomatosis. In ductal hyperplasia, both epithelial and myoepithelial cells proliferate giving the impression of a heterogeneous population of cells (Slide 12). There is a mild irregularity in nuclear size and shape.

Based on the architecture, ductal hyperplasia is graded as mild, and moderate (or florid). In the latter, solid pattern predominates.

In the presence of architectural and nuclear atypicality, the ductal hyperplasia is designated as atypical ductal or lobular hyperplasia. These atypical hyperplasias are defined as having some but not all the morphologic features of carcinoma in situ.

In atypical ductal hyperplasia, the proliferating atypical cells have enlarged, irregular, hyperchromatic nuclei, and small nucleoli (Slides 13-14-15-16). They are mixed with the normal secretory or myoepithelial cells without reaching to a homogeneous population of atypical cells expected of a ductal carcinoma in situ (Page and Anderson).

It is common for ductal and atypical ductal hyperplasias to undergo focal stromal fibrosis, elastosis, and hyalinization producing stellate shaped, indurated lesions, the so called radial scar. This lesion will be discussed in a later section along with papilloma.

Atypical lobular hyperplasia is characterized by partial expansion of the lobules and the atypical cells are loosely cohesive. Their nuclei are slightly larger than the normal cells, slightly irregular in shape and variable in size. The chromatin particles are fine chromatin particles and the nucleoli are small. In the background, myoepithelial cells, although reduced in number, can still be identified (Slides 17 and 18) (Page and Anderson).

In lobular carcinoma in situ, the lobules are expanded and solidly filled by atypical cells. The myoepithelial cells are absent, except a few in the periphery of the lobules.

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C. Adenosis

Adenosis refers to a spectrum of changes within the lobules beginning from the hyperplasia to the subsequent fibrosis and calcifications. The term adenosis tumor is used by some authors, when the adenosis presents as a mass.

In the early stage of adenosis, the lobules are enlarged with an increased number of acini (Slides 19 and 20). Later, myoepithelial proliferation and stromal fibrosis cause distortion of the individual acini, the so called sclerosing adenosis (Slides 21 and 22). Within the acini, laminated, purple, psammoma bodies often occur (Slide 22). A compressed, cord-like arrangement sometimes simulate invasive carcinomas. Although the lobular borders become irregular, the lobules remain intact (Slides 21 and 23). With further stromal fibrosis and atrophy, the acini become few in number and the lobules become small (Slides 23 and 24).

It is important to appreciate the lobular pattern under low power magnification. On high power, the preservation of the basement membrane and normal two cell layer of the acini is indication of benignancy.

Microglandular adenosis is typically seen in postmenopausal women. Clusters of round glandular profiles occur in the adipose tissue (Slide 25). This feature and a single layer of lining cells sometimes lead to an erroneous diagnosis of tubular carcinoma (Slide 26).

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D. Fibrosis (Fibrous Mastopathy)

Fibrosis or fibrous mastopathy is an increase of fibrous connective tissue, which is usually hypo- to acellular. The lobules in particular are reduced in number and in size (Slide 27). Focal fibrosis may present as a palpable mass or as an impalpable mammographic abnormality. A variant of fibrosis occurs in some women with a long history of insulin-dependent diabetes mellitus, referred to as diabetic fibrous breast disease.