General Pathology 601 for Dental Students

Pathology of the Breast 

Margaret M Grimes, MD Surgical Pathology Sanger Hall, 5th Floor (804) 828-9739 mmgrimes@vcu.edu

Objectives
Upon completion of this lecture you will be able to:

1. Describe the pathogenesis of proliferative and nonproliferative fibrocystic changes of the breast.
2. Describe the major differences between duct carcinoma in situ (DCIS or intraductal carcinoma) and lobular carcinoma in situ (LCIS).
3. List clinical presentations of invasive duct carcinoma.
4. Identify the most important predictors of disease-free and overall survival in invasive breast cancer.
5. Recognize prognostic factors in breast carcinoma.

Important Terms
Ducts, ductules and lobules
Acute mastitis
Fat necrosis
Gynecomastia
Fibroadenoma
Her-2/neu (c-erb-B2)

Normal Breast Structure

The female breast is composed of 6 to 10 major duct systems, each comprising numerous lobules. A lobule consists of terminal ductules and acini. Terminal ductules empty into ducts. Ducts and ductules are lined by a two-cell layer: inner epithelial cells and outer myoepithelial cells. The latter have contractile properties and assist in expelling milk. The largest ducts drain into the lactiferous ducts and sinuses, which then drain onto the nipple. The lobules and ducts are surrounded by supporting stroma and abundant adipose tissue.

Lactational change associated with pregnancy is related to progesterone levels. Numerous true secretory glands develop from the terminal ductules. These are lined by vacuolated cells that secrete colostrum, and later, milk.

Atrophy, or involution, occurs in the postmenopausal state due to the absence of influence of estrogen and progesterone. The histologic appearance is variable. Generally, there is a loss of lobules, and replacement of stroma by adipose tissue. In some individuals there is an increase in periductal fibrous tissue.

The normal male breast differs in structure from the female breast in that there are no acini. The breast consists of ductal structures surrounded by a small amount of adipose and fibrous tissue.

Benign Non-Neoplastic Diseases of the Breast

Acute mastitis
Consists of a localized or diffuse acute inflammation of the breast, sometimes associated with the development of an abscess. This process is usually caused by Staphylococcus aureus. Predisposing factors include postpartum nursing and dermatologic conditions of the nipple.

Fat necrosis
Is usually caused by trauma to the breast. Disruption of fat cells is accompanied by a histiocytic response and eventually fibrous scarring. The clinical importance is that this may present as a hard mass that can be suspicious for carcinoma on physical examination. Histologically, there are two microscopic phases:

1. Acute phase: clear lipid-filled spaces surrounded by "foamy" histiocytes and some lymphocytes.
2. Healed phase: dense fibrous scar

Gynecomastia
Of the male breast is enlargement of one or both breasts caused by excessive estrogen stimulation. Predisposing factors include:

• hormonal imbalance, as may occur in puberty or old age
• exogenous hormones
• drugs, including dilantin, digitalis, marijuana
• Klinefelter's syndrome (testicular feminization)
• testicular tumors
• liver disease

Microscopic features of gynecomastia are ductal epithelial hyperplasia, stromal edema, and loose fibrosis around ducts.

Fibrocystic changes of the female breast consist of a variety of gross and histologic changes that represent exaggerated responses to fluctuating levels of estrogen and progesterone. This is the most common benign condition of the adult female breast. Clinically, the changes are usually bilateral, and may produce firm lumps or bumps, or fluctuant cysts. Microscopically, there are two major forms: non-proliferative and proliferative.

• Cysts result from dilation of ductules
• Apocrine metaplastic epithelium resembles that of apocrine sweat glands
• Adenosis is expansion of the TDLU

Proliferative
Changes include: sclerosing adenosis, duct epithelial hyperplasia, lobular epithelial hyperplasia, atypical ductal hyperplasia, atypical lobular hyperplasia.

• In sclerosing adenosis there is increased fibrosis within expanded lobules, with distortion and compression of the epithelium

• In duct or lobular hyperplasia, there is a proliferation of the epithelium lining these structures

• In atypical hyperplasia, there is not only a proliferation of the epithelium but also cytologic and architectural atypia

Certain types of fibrocystic changes have been associated with an increased risk for the development of invasive breast carcinoma, while other types have no apparent association. The following is a list of fibrocystic changes and their risks (risk is compared to women who have not had a breast biopsy):

No increased risk:

• adenosis
• fibrosis
• mild hyperplasia without atypia
• gross or microscopic cysts
• apocrine metaplasia

Slightly increased risk (1.5 - 2.0 times):

• moderate hyperplasia without atypia
• sclerosing adenosis

Moderately increased risk (4.0 - 5.0 times):

• atypical ductal hyperplasia
• atypical lobular hyperplasia

Benign Neoplasms of the Female Breast

Fibroadenoma is the most common tumor of the breast. It usually occurs as a unilateral lesion in young women. Clinically, it presents as a firm, rounded, mobile mass. The gross pathologic appearance is that of  well-circumscribed mass, usually 2 to 4 cm. in diameter, having an tan-white, whorled, firm cut surface. Microscopically, the tumor is composed of a loose to dense stroma with variable numbers of fibroblasts and myofibroblasts, and branching ducts.

Intraductal papilloma presents as a subareolar lump, sometimes associated with a bloody nipple discharge. Grossly, it consists of a small papillary mass within a cystically dilated duct. Microscopically, there are usually numerous branching fibrovascular stalks lined by columnar epithelium.

In Situ Carcinoma of the Breast

In this process, cytologically malignant cells replace the normal epithelial cells lining the ducts or lobules. These cells are confined by the basement membrane of these structures and at this point have not invaded the breast stroma or lymphatics, and cannot metastasize.

There are two major types:

1. Duct carcinoma in situ (DCIS or intraductal carcinoma)
2. Lobular carcinoma in situ (LCIS).

Microscopically, DCIS is typically composed of ducts filled with atypical epithelial cells with large nuclei, nucleoli, and mitotic figures. There may be necrotic debris filling the lumen (comedocarcinoma), and microcalcifications may be found in the necrotic debris, in adjacent stroma, or in adjacent benign ducts.

In LCIS, lobules are expanded by a uniform population of small yet atypical cells. Usually the process obliterates the lumens of the acini.

Major differences between these two types include:

DCIS and LCIS are associated with a markedly increased risk (8.0 to 10.0 times) of developing invasive cancer, compared with women who have not had a breast biopsy.

Invasive Carcinoma of the Breast

Invasive duct carcinoma
This is the most common type of breast cancer, accounting for approximately 75% of cases. It occurs most frequently in middle-aged to elderly women, and rarely in males. Increased risk is associated with early menarche, late menopause, nulliparity, late first live birth, and first-degree relative with breast cancer. Possible clinical presentations include:

• hard, fixed mass
• "peau d' orange" change of overlying skin
• ulceration of overlying skin
• bloody nipple discharge
• inverted or retracted nipple
• Paget's disease of the nipple (see below)
• Mammographic abnormality

With the increased use of screening mammography, advanced clinical presentations are less common than in previous years. Patients are now frequently diagnosed with small tumors detected as abnormal densities or microcalcifications on mammogram.

The gross appearance of invasive duct carcinoma is a hard, gritty mass with ill-defined margins. There may be yellow-white chalky streaks within the lesion. Microscopically, there are irregular duct-like structures or solid nests of malignant cells infiltrating the breast tissue. Often the infiltrating tumor cells are accompanied by a desmoplastic (fibroblastic) reaction in the stroma. There may be foci of DCIS present within or adjacent to the infiltrating tumor.

Paget's disease of the nipple occurs in association with an underlying DCIS or invasive duct carcinoma. Clinically, the nipple is crusted, red, sometimes with fissures or oozing. This process is sometimes mistaken for a dermatologic problem such as eczema. On histologic examination, there are malignant cells lying singly or in groups within the epidermis of the nipple. These cells often contain intracytoplasmic mucin, and stain positively for carcinoembryonic antigen, features that identify them as malignant duct cells.

Patterns of spread of breast carcinoma
Breast carcinoma cells spread through lymphatics to regional and distant lymph nodes. Tumor cells may also spread hematogenously and patients may present with metastases in the viscera and bones.

Prognostic factors in breast carcinoma

	Better prognosis	Worse prognosis
Tumor size	<2 cm.	>2 cm.
Tumor grade	well differentiated	poorly differentiated
Estrogen receptors	present	absent
Positive axillary nodes	none or few	many
Her-2/neu	negative	positive

Her-2/neu (also known as c-erb-B2) is an oncogene encoding a membrane-bound growth receptor protein. Over-expression of this protein by invasive breast carcinomas has been associated with poorer prognosis compared with Her-2/neu negative tumors.

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Updated September 5, 2007