Breast Cancer Review

A basic knowledge of breast structure and development is essential for performing an effective clinical breast examination. Likewise, a familiarity with the various types of benign and malignant changes of the breast is key for understanding the broader issue of breast cancer and its management.

Breast Structure

The breast lies between the second and sixth ribs, from the sternal edge to the edge of the axilla, and against the pectoralis muscle on the chest wall. Breast tissue also projects into the axilla as the tail of Spence. For clinical purposes, the breast is divided into four quadrants: upper inner, upper outer, lower inner and lower outer quadrants. Cancer occurs most often in the upper outer quadrant.

The breast is composed of 15-20 lobes that radiate from the nipple. Each lobe is surrounded by fat and fibrous connective tissue and is divided into many lobules. The lobule (sometimes called the ductal-lobular unit) is the basic structural unit of the breast and is lined by epithelial cells. Each lobule is subdivided into 10 to 100 alveoli, the milk producing units of the breast. Milk flows from the alveoli of the lobules into the ducts. The ducts gradually coalesce into 10 to 15 major ducts; each lobe containing one major duct terminating in the nipple.

The most common type of breast cancer is a carcinoma that originates in epithelial cells. About 85% of breast carcinomas originate within the cells of the ducts (ductal carcinoma); the remaining 15% begin in the cells that line the lobules (lobular carcinoma). Non-carcinomatous breast cancers are rare and originate in the connective tissues of the breast.

Breasts also contain blood and lymphatic vessels. Most lymphatic vessels within the breast lead to axillary lymph nodes. Some also connect to supra- or infraclavicular nodes, and internal mammary nodes. Cancer cells may enter lymphatic vessels and spread to lymph nodes. Cancer cells may also enter blood vessels and spread to other parts of the body.

Beneath the tissues of the breast lie the muscles of the chest wall and between the two is the fascia (a layer of connective tissue). Two layers of suspensory ligaments (Cooper’s ligaments) link the breast to the fascia, providing support. As these ligaments stretch with age or weight gain, the breast loses some of its firmness.

Breast Development

Breast tissue begins to develop around the sixth week in utero with the formation of the mammary ridge. Also called the mammary fold or milk line, this thickening of the skin extends from just below the axilla to the inguinal region (groin area). It then recedes before birth, leaving two primary breast buds on the upper half of the chest. In newborns, the nipples and beginnings of the milk duct system are present. This rudimentary system remains essentially at rest until puberty. For females, usually around the ages of 10 or 11, the release of ovary producing hormones (estrogen and progesterone) stimulates further development of the ducts and lobules. At the same time, increases in adipose tissue (fatty tissue) and fibrous connective tissue cause the breasts to enlarge. By adulthood, all glandular elements are fully formed and breast development is complete. At menopause, the lobules recede, leaving mostly ducts, adipose and fibrous tissue. Histologically, postmenopausal and prepubertal breasts are very similar.

Throughout a woman's life, breast tissue remains sensitive to hormonal changes, including those that occur during menstruation, pregnancy and lactation. During each menstrual cycle, levels of estrogen and progesterone rise, causing ducts and milk glands to enlarge. In pregnancy, rising hormonal levels cause further branching and differentiation of the ducts and lobules, accompanied by an increase in adipose tissue and richer blood flow. With lactation, lobules become dilated and engorged with colostrum and milk. Lactation also increases the possibility of abnormal nipple discharge, infection and inflammation, although nonlactating women may also experience these types of benign breast changes.

Benign Changes

Benign breast changes refer to a heterogeneous group of lesions which can be divided into two major types: inflammatory (including infectious, traumatic, etc.) and benign epithelial lesions (also known as fibrocystic changes). Both hormones and genetics are believed to play causal roles in benign breast changes. Some lesions are palpable while others are detectable only with breast imaging or biopsy. Many appear similar to breast cancer, yet the vast majority of lumps, inflammations, nipple discharges and other breast changes are neither cancerous nor rare. In fact, benign changes of the breast are very common. According to the American Cancer Society, if breast tissue is examined under a microscope, benign breast changes can be found in as many as 9 out of 10 women.¹ The most common types are those described as fibrocystic changes.

The exact cause of fibrocystic changes is not completely understood but is known to be associated with hormonal activity. These types of changes may vary during the menstrual cycle and usually subside with menopause. Symptoms of fibrocystic changes include lumps, lumpiness, areas of thickening, and tenderness.

Fibrocystic changes are often grouped into three descriptive subtypes, based upon the appearance of tissue cells under a microscope. Each of the following subtypes confers differing relative risks for developing into subsequent breast cancer:

Nonproliferative changes include histologic findings as various as cysts, nonsclerosing adenosis, ductal ectasia, lactational adenoma, simple fibroadenoma, and mild hyperplasia, among others. In women with nonproliferative breast changes, the risk of subsequent breast cancer is about the same as that of the general population. Over the next 15 years, 6% of cases diagnosed as nonproliferative breast lesions will develop into breast cancer compared to 5% of the general population.²

Proliferative changes without atypia is characterized by excessive cell growth, especially of the duct linings, but with no cells appearing abnormal. Cells show few genetic changes. Examples include intraductal papilloma, radial scar, sclerosing adenosis, complex fibroadenoma, and moderate or florid hyperplasia. Proliferative breast changes without atypia is associated with a slightly elevated risk of developing breast cancer - approximately 1.5 to 2.0 times that of the general population. Over the next 15 years, 10% of these cases will develop into breast cancer.³

Proliferative changes with atypia is characterized by excessive cell growth with some cells appearing abnormal. Cells show genetic changes that could make them potentially invasive. Both atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH) may be difficult to differentiate from carcinoma - either ductal carcinoma in situ (DSIS) or lobular carcinoma in situ (LCIS). Atypical hyperplasia carries an approximate 4.0 to 5.0 times increase in the relative risk of developing breast cancer. For every 100 cases of atypia, 19 are expected to develop into breast cancer over the next 15 years.⁴

Benign lesions are usually confirmed by imaging tests or biopsy. Thus, every irregularity should be brought to the attention of a healthcare provider for conclusive diagnosis. Whether or not treatment is required depends upon a number of factors including the exact nature of the diagnosis, a woman's discomfort, and the potential of the lesion for developing into breast cancer.

Types of Breast Cancer

Cancer is a process in which normal cells go through stages that eventually change them to abnormal cells that multiply out of control. Many breast cancers arise from a sequence that begins with an increase in the number of breast cells (hyperplasia) to the emergence of atypical breast cells (atypical hyperplasia) followed by carcinoma in situ (noninvasive cancer) and finally, invasive cancer. Not all breast cancers necessarily follow this progressive pattern, however. And, the speed of progression for those that do is highly variable. It also appears that some cancers may never progress beyond in situ disease.

Ductal carcinoma in situ (DCIS) is the most common type of noninvasive breast cancer, accounting for about 15% of all new breast cancer cases in the U.S.⁵ The term in situ means in place, so ductal carcinoma in situ refers to an uncontrolled growth of cells that are confined to the breast duct. As such, some experts believe DCIS to be a precancerous condition. Others, however, classify any cellular changes beyond atypical hyperplasia as cancer. Frequently a single lesion, DCIS is classified into several histological subtypes associated with varying prognostic implications. Invasive cancer usually occurs within the same breast, but women with DCIS are also at higher risk of developing cancer in the opposite breast. Very few cases of DCIS present as a palpable mass; most are diagnosed by mammography, usually as clustered microcalcifications. DCIS may also present as pathologic nipple discharge, with or without a mass. The frequency of diagnosis of DCIS has greatly increased with greater use of mammography. With early detection and treatment, the five-year survival rate for DCIS is nearly 100%, providing that the cancer has not spread past the milk ducts.⁶

Lobular carcinoma in situ (LCIS) is characterized by abnormal changes in the cells that line the milk-producing lobules, or lobes, of the breast. LCIS is much less common (accounting for only about 4,200 cases annually in the United States)⁷ and carries slightly less risk of invasive cancer than DCIS. Also called lobular intraepithelial neoplasia, LCIS is actually considered by most medical experts to be neither cancer nor a premalignant lesion, but rather a marker that identifies women at increased risk of invasive breast cancer. Risk remains elevated beyond two decades and most subsequent breast cancers are ductal rather than lobular. LCIS typically includes multiple lesions and is frequently bilateral. It is usually discovered as an incidental finding from breast biopsy; there are rarely clinical or mammographic signs.

Invasive (infiltrating) ductal carcinoma (IDC) is the most common type of breast cancer. About 80% of invasive breast cancers are classified as invasive ductal carcinoma.⁸ Also called infiltrating ductal carcinoma, cancer cells have penetrated the ductal wall and invaded surrounding breast tissue. The cells may then metastasize to other parts of the body through the bloodstream or lymphatic system. IDC may present as a hard and firm palpable mass or as a mammographic abnormality. Tumors can cause skin and nipple retraction. IDC is most commonly encountered in pure form, although a substantial minority of IDC cases exhibit a combination of histologic types. As with all invasive breast cancers, it is important to detect and treat invasive ductal carcinoma early, before it has had an opportunity to metastasize.

Invasive (infiltrating) lobular carcinoma (ILC) begins in the milk-producing lobules where it extends into the adipose tissue of the breast. It is relatively uncommon, comprising about 10% of invasive breast cancers.⁹ As with IDC, ILC may present as a palpable mass, however, it tends to be less well-defined. Often, the only clinical evidence is that of a vague area of thickening. ILC can also be more difficult to detect by mammogram. Compared with IDC, patients with infiltrating lobular carcinoma are more often prone to bilateral disease.

Tubular carcinoma is a highly differentiated invasive carcinoma whose cells are regular and arranged in well-defined tubules. Before widespread use of mammography, tubular carcinomas were most often detected as palpable lesions. Now, most cases present as nonpalpable mammographic abnormalities, usually a mass lesion, and only occasionally associated with microcalcifications. Some are discovered incidentally in biopsies performed for unrelated reasons. Reported incidence in mammographically screened populations range from about 8% to as high as 27%.¹⁰ Pure tubular carcinoma has limited metastatic potential and better than average prognosis.

Medullary carcinoma is a relatively uncommon type of invasive carcinoma, accounting for less than 5% to 7% of all invasive breast cancers.¹¹ Lesions have well-defined boundaries and can be quite large and soft on palpation. Histologically, the tumor is characterized by larger than average cancer cells, and with immune system cells present on the edges of the tumor. The prognosis for this type of breast cancer is relatively favorable.

Mucinous carcinoma, also called colloid carcinoma, is an invasive form of breast cancer characterized by large amounts of extracellular mucin production. Less than 5% of invasive breast cancers show a mucinous component.¹² Usually occurring in postmenopausal women, tumors may or may not be palpable. Mammographically, pure mucinous carcinomas may mimic benign lesions with well-circumscribed and microlobulated margins. Like medullary carcinoma, mucinous carcinoma is associated with a relatively favorable prognosis.

Metaplastic carcinoma is uncommon, representing less than 5% of all breast cancers.¹³ Lesions contain several different types of cells that are not typically seen in other forms of breast cancer. Clinical presentation is frequently a single palpable lesion often associated with rapid growth. Mammographically, most metaplastic carcinomas are fairly circumscribed, noncalcified lesions which, in some cases, appear benign. Prognostic implications of this type of breast cancer are variable.

Invasive cribriform carcinoma is a well-differentiated cancer comprised of small and uniform cells. It shares some features with tubular carcinoma and is also associated with better than average prognosis. Roughly 5% to 6% of invasive breast cancers show at least a partial invasive cribriform component..¹⁴

Invasive papillary carcinoma is very rare, comprising less than 1% to 2% of invasive breast cancers.¹⁵ Found predominantly in postmenopausal women, it is characterized by nodular densities that may be multiple and are frequently lobulated. Limited data suggests relatively favorable prognosis.

Invasive micropapillary carcinoma is a distinct but poorly recognized variant of breast cancer, usually presenting as a firm, immobile mass. Findings on mammography are of a spiculated, irregular or round, high density mass with or without associated microcalcifications. Pure micropapillary carcinoma is uncommon, with an incidence of less than 3%.¹⁶ Limited research suggests that this type of cancer may be associated with a relatively poor prognosis.

Inflammatory breast cancer is a form of locally advanced breast cancer associated with a rapid onset of clinical features including breast inflammation, warmth, thickening or dimpling (peau d' orange), and a palpable ridge at the margin of induration. Often mistaken as an infection, symptoms result from the blocking of lymphatic vessels near the surface of the skin by cancer cells. Inflammatory breast cancer is relatively rare, representing about 1% to 5% of all breast cancers in the U.S.,¹⁷ and has a less favorable than average prognosis.

Paget’s disease of the nipple begins in the milk ducts as either an in situ or invasive cancer; prognosis is excellent when associated with carcinoma in situ. Early stage symptoms include erythema and mild scaling of the nipple skin. Symptoms of more advanced disease may include nipple tingling, itching, increased sensitivity, burning, pain or oozing. Diagnosed by biopsy, Paget's disease of the nipple must be differentiated from eczema, contact dermatitis, basal cell carcinoma, and a number of other conditions. Paget's disease of the nipple accounts for approximately 1% of all breast cancers.¹⁸

Phylloides tumors (also spelled phyllodes) can be either benign, borderline or malignant. Malignant tumors are very rare. Phylloides tumors are biphasic and composed of benign epithelial elements and cellular connective tissue stroma. The stroma dictates whether the tumor will be benign, borderline or malignant. They can grow to a relatively large size within a few months, although rapid growth does not necessarily indicate malignancy. The gross appearance of most phylloides tumors, particularly those that are benign, is not distinctly different from fibroadenomas. They can also be difficult to distinguish from fibroadenomas on fine-needle aspiration and on core biopsy. Phylloides tumors are often painless.

Health providers seeking additional information about these and other rarer forms of breast cancer - including clinical presentation, gross pathology, histopathology, clinical course and prognosis - are referred to Diseases of the Breast (3rd edition) by Jay Harris, et al (Eds), 2004. Online sources of additional information can be found on the References and Additional Resources page.

¹American Cancer Society. Benign Breast Conditions (revised, May 15, 2003). Retrieved May 7, 2006 at: http://www.cancer.org/docroot/CRI/content/CRI_2_6X_Benign_Breast_Conditions _59.asp

²Mayo Clinic. Breast Biopsy: Interpreting Your Risk for Breast Cancer (Aug. 5, 2005). Retrieved Apr. 10, 2006 at: http://www.mayoclinic.com/health/breast-biopsy/WO00111 See also: National Cancer Institute. Benign Breast Disease Indicates Relative Risk for Breast Cancer. NCI Bulletin. 2005 Jul;30(2). Retrieved Apr. 13, 2006 at: http://www.cancer.gov/ncicancerbulletin/NCI_Cancer_Bulletin _072605/page5

⁶Imaginis.Common Forms of Breast Cancer (updated, May, 2006). Retrieved July 7, 2006 at: http://66.223.111.234/breasthealth/breast_cancer2.asp

Anatomy and Pathology

Introduction

Breast Structure

Breast Development

Benign Changes

Types of Breast Cancer