Hacker & Moore's Essentials of Obstetrics and Gynecology: With STUDENT CONSULT Online Access,5th ed.

Chapter 29

Breast Disease: A Gynecologic Perspective

Neville F. Hacker, Michael L. Friedlander

It is important that gynecologists be expert in breast examination, diligent about screening asymptomatic women for breast cancer, familiar with common benign and malignant disorders of the breast, and conversant with the various therapeutic options. In a number of centers in the world, gynecologic oncologists treat breast cancer.

image Screening of the Breast in Asymptomatic Women

SELF-EXAMINATION

Many breast cancers are detected by women themselves, and monthly breast self-examination should be promoted. Written information should be supplemented by practical training. There is no solid evidence that breast self-examination reduces breast cancer mortality, but it is reasonable to assume that a woman’s increased awareness of her own breasts may lead to an earlier diagnosis.

Breast Self-Examination Technique

The patient may be invited to perform the examination after each menstrual period. She should commence the technique in the upright position, carefully inspecting the breasts initially with her arms by her sides and then with her arms raised above her head. She should palpate the supraclavicular and axillary regions for the presence of nodes. The patient should then lie down and systematically palpate each quadrant of the breast against the chest wall, using the flat of her fingers. Finally, she should palpate the areolar areas and then compress the nipples for evidence of secretion.

Breast Examination by Physician

A complete breast examination should be performed by a physician at least annually. The breasts are first inspected with the patient in an upright position. The contour and symmetry are observed, and any skin changes or nipple retraction is noted. Skin retraction, because of tethering to an underlying malignancy, may be highlighted by having the patient extend her arms over her head.

Palpation of the breast, areola, and nipple is performed with the flat of the hand. If any mass is palpated, its fixation to deep tissues should be determined by asking the patient to place her hands over her hips and contract her pectoral muscles. Each axilla is then carefully examined while the patient’s arm is supported. The supraclavicular fossae are also palpated for lymphadenopathy. After palpation in the upright position, the examination is repeated in the supine position.

MAMMOGRAPHY

Radiologic examination of the breast is an important component of the screening process carried out in asymptomatic women and should be performed in conjunction with a thorough physical examination. Densities and fine calcifications constitute suspicious findings, and clinically inapparent malignancies less than 1 cm in diameter may be detected.

Mammograms of high quality can be made with about 0.3 cGy or less of radiation, so there is little, if any, risk for this technique causing breast cancer.

In the Breast Cancer Detection Demonstration Project carried out by the American Cancer Society and the National Cancer Institute, 89% of 3557 cancers were correctly identified by mammography, 42% of which were not clinically detectable.

The American Cancer Society recommends annual mammograms starting at age 40 years.

ULTRASONOGRAPHY

Ultrasonography can differentiate cystic from solid masses and may demonstrate solid tissue that is potentially malignant within or adjacent to a cyst. It is also useful for imaging palpable focal masses in women younger than 30 years, reducing the need for x-ray studies in this population.

MAGNETIC RESONANCE IMAGING

Magnetic resonance imaging is a useful adjunct in breast imaging. Reported advantages include improved staging and treatment planning, enhanced evaluation of the augmented breast, better detection of recurrences, and possibly improved screening of high-risk women.

image Diagnosis of Breast Lesions

Physiologic nodularity and cyclic tenderness caused by the changing hormonal milieu must be distinguished from benign or malignant pathologic changes. Definitive diagnosis of breast neoplasms may be made by open biopsy or by fine-needle (22-gauge) aspiration cytology.

FINE-NEEDLE BIOPSY

Fine-needle aspiration biopsy of the palpably suspicious lump in the breast can be performed in the outpatient clinic. Smears are prepared from the aspirate to allow cytologic evaluation. In experienced hands, the test is both sensitive and specific. A negative result should never be accepted as definitive when there are clinical or mammographic indications that the lesion may be malignant. In the presence of a palpable lump, fine-needle aspiration cytology should make it possible to diagnose breast cancer without formal excisional biopsy in about 90% of cases, allowing the definitive management of the patient to be discussed preoperatively.

OPEN BREAST BIOPSY

Small masses may undergo excisional biopsy, whereas large masses should undergo incisional biopsy, or occasionally core-cutting needle biopsy. Absolute indications for open breast biopsy are listed in Box 29-1. Relative indications for breast biopsy include those women with a clinically benign mass but a positive family or personal history of breast cancer, a history of atypical hyperplasia, or an equivocal finding on mammography or cytology.

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BOX 29-1 Absolute Indications for Open Breast Biopsy

• Clinically suspicious (dominant) mass that persists through a menstrual cycle, regardless of mammographic findings; if fine-needle aspiration cytology is unequivocally positive, most surgeons proceed directly to definitive treatment.

• Cystic mass that does not completely collapse on aspiration (residual solid component) or that contains bloody fluid.

• Spontaneous serous or serosanguineous nipple discharge; in the absence of a mass, a “trigger point” should be demonstrable.

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Open breast biopsy may be performed as an outpatient procedure under local anesthesia or as an inpatient procedure under general anesthesia. Women with large breasts who have small, deeply situated lesions are not good candidates for outpatient biopsies, nor are those who have a nonpalpable lesion detected by mammography.

image Common Benign Breast Disorders

FIBROCYSTIC CHANGES

The earlier term fibrocystic disease has little clinical value, and the term was abandoned by the College of American Pathologists in 1985. Lesions formerly grouped together under the designation of fibrocystic disease represent a pathologically heterogeneous group of diseases that can be divided into three separate histologic categories: nonproliferative lesions, proliferative lesions (hyperplasia) without atypia, and atypical hyperplasias.

HYPERPLASIA

Hyperplasia is the most common benign breast disorder and is present in about 50% of women. Histologically, the hyperplastic changes may involve any or all of the breast tissues (lobular epithelium, ductal epithelium, and connective tissue). When the hyperplastic changes are associated with cellular atypia, there is an increased risk for subsequent malignant transformation.

It is postulated that the hyperplastic changes are caused by a relative or absolute decrease in production of progesterone or an increase in the amount of estrogen. Estrogen promotes the growth of mammary ducts and the periductal stroma, whereas progesterone is responsible for the development of lobular and alveolar structures. Patients with hyperplasia improve dramatically during pregnancy and lactation because of the large amount of progesterone produced by the corpus luteum and placenta and the increased production of estriol, which blocks the hyperplastic changes produced by estradiol and estrone.

The disorder usually occurs in the premenopausal years. Clinically, the lesions are usually multiple and bilateral and are characterized by pain and tenderness, particularly premenstrually.

Treatment depends on the age of the patient, the severity of the symptoms, and the relative risk for the development of breast cancer. Women older than 25 years should undergo baseline mammography to exclude carcinoma. Cysts may be aspirated to relieve pain (Figure 29-1). If the fluid is clear and the lump disappears, careful follow-up only is indicated. Open biopsy is required if the fluid is bloody or if there is any residual mass following aspiration.

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FIGURE 29-1 Aspiration of a breast cyst. Ultrasound may be used to differentiate a solid from a cystic breast mass.

FIBROADENOMA

Composed of both fibrous and glandular tissue, the fibroadenoma is the most common benign tumor found in the female breast. Clinically these tumors are sharply circumscribed, freely mobile nodules that may occur at any age but are common before the age of 30 years. They usually are solitary and generally are removed when they reach 2 to 4 cm in diameter, although giant forms up to 15 cm in diameter occasionally occur and have malignant potential. Pregnancy may stimulate their growth, and regression and calcification usually eventuate postmenopausally. These larger tumors require surgical excision for definitive diagnosis and cure.

INTRADUCTAL PAPILLOMA

Papillary neoplastic growths may develop within the ducts of the breast, most commonly just before or during menopause. They are rarely palpable and are usually diagnosed because of a bloody, serous, or turbid discharge from the nipple. Mammography and cytologic examination of the fluid are helpful in investigating nipple discharge. Excisional biopsy of the lesion and involved duct is the treatment of choice.

Histologically there is a spectrum of lesions ranging from those that are clearly benign to those that are anaplastic and give evidence of invasive tendencies.

GALACTOCELE

A galactocele is a cystic dilation of a duct that is filled with thick, inspissated, milky fluid. It presents duringor shortly after lactation and implies some cause for ductal obstruction, such as inflammation, hyperplasia, or neoplasia. Often multiple cysts are present. Secondary infection may produce areas of acute mastitis or abscess formation. Needle aspiration is usually curative. If the fluid is bloody or the mass does not disappear completely, excisional biopsy is required.

image Breast Cancer

Breast cancer is the most common female malignancy, accounting for 26% of malignancies in women. It is second only to lung cancer as the leading cause of cancer deaths in women. More than 175,000 new cases are diagnosed annually in the United States, and about 40,000 of these women die from the disease. In the United States, there is a 1 in 8 chance that a woman will develop breast cancer during her lifetime, if she lives to 90 years of age.

ETIOLOGY

Established risk factors for breast cancer are shown in Table 29-1, but 75% of women develop the disease despite having no apparently increased susceptibility.

TABLE 29-1 ESTABLISHED RISK FACTORS FOR BREAST CANCER

Risk Factor

Relative Risk

Age (≥50 vs <50 yr)

6.5

Family history of breast cancer

First-degree relative

1.4-13.6

Second-degree relative

1.5-1.8

Age at menarche (<12 vs ≥14 yr)

1.2-1.5

Age at menopause (≥55 vs <55 yr)

1.5-2.0

Age at first live birth (>30 vs <20 yr)

1.3-2.2

Benign breast disease

Breast biopsy (any histologic finding)

1.8-10.5

Atypical hyperplasia

4.0-4.4

Hormone replacement therapy

1.0-1.5

Data from Armstrong K, Eisen A, Weber B: Assessing the risk of breast cancer. N Engl J Med 342:564-571, 2000.

The incidence and mortality rates for breast cancer are about 5 times higher in North America and northern Europe than they are in many Asian and African countries. Migrants to the United States from Asia (principally Chinese and Japanese) do not experience a substantial increase in risk, but their first-generation and second-generation descendants have rates approaching those of the white population in the United States. The difference may be related to dietary customs.

Menopausal hormone replacement therapy appears to produce a small increased risk for breast cancer, and the estrogen-progestin regimen increases the risk beyond that associated with estrogen alone.

About 5% to 10% of breast cancer cases are hereditary, resulting from mutations in the BRCA1 or BRCA2 gene. These genetic mutations also increase the risk for ovarian cancer. Hereditary breast cancer is particularly common in premenopausal women. Women with a mutated BRCA1 or BRCA2 gene have up to a 70% risk for developing breast cancer by 65 years of age.

TUMOR TYPES

The mammary epithelium gives rise to a wide variety of histologic tumor types. About 80% of all breast cancers are nonspecific infiltrating ductal carcinomas. These tumors usually induce a significant fibrotic response and are stony hard to clinical palpation. Less common types include lobular, medullary, mucinous, tubular, and papillary. In many tumors, several patterns coexist.

Paget’s disease of the breast occurs in about 3% of breast cancer patients. It represents a specialized form of intraductal carcinoma that arises in the main excretory ducts of the breasts and extends to involve the skin of the nipple and areola, producing an eczematoid appearance. The underlying carcinoma, although invariably present, can be palpated clinically in only about two thirds of patients.

Inflammatory breast cancer represents 1% to 4% of cases and is often seen in pregnancy. It is characterized clinically by warmth and redness of the overlying skin and induration of the surrounding breast tissues.Biopsies of the erythematous areas reveal malignant cells in subdermal lymphatics, causing an obstructive lymphangitis. Inflammatory cells are rarely present. Most patients have signs of advanced cancer at the time of diagnosis, including palpable regional lymph nodes and distant metastases.

TUMOR SPREAD

Breast cancer spreads by local infiltration as well as by lymphatic or hematogenous routes. Locally, the tumor infiltrates directly into the breast parenchyma, eventually involving the overlying skin or the deep pectoral fascia.

Lymphatic spread is mainly to the axillary nodes, involvement of which occurs in up to 50% of patients with symptomatic breast cancer and in 10% to 20% of patients with screen-detected breast cancers. The second major area for lymph node metastases is the internal mammary node chain. These nodes are most likely to be involved when the primary lesion is medially or centrally situated. The supraclavicular nodes are usually involved only after axillary node involvement.

Hematogenous spread occurs mainly to the lungs and liver, but other common sites of involvement include bone, pleura, adrenals, ovaries, and brain.

STAGING

Several systems of staging for cancer of the breast have been recommended. The one recommended by the American Joint Committee on Cancer is available at http://www.cancerstaging.org.

CLINICAL FEATURES

Carcinoma of the breast is usually painless and may be freely mobile. A serous or bloody nipple discharge may be present. With progressive growth, the tumor may become fixed to the deep fascia. Extension to the skin may cause retraction and dimpling, whereas ductal involvement may cause nipple retraction. Blockage of skin lymphatics may cause lymphedema and thickening of the skin, a change referred to as peau d’orange (Figure 29-2) due to its “orange peel” appearance.

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FIGURE 29-2 Carcinoma of the breast. Note the nipple retraction and the peau d’orange appearance.

(From Swartz MH: Textbook of Physical Diagnosis, 5th ed. Philadelphia, Saunders, 2006.)

TREATMENT

With increasing awareness of the likelihood of early hematogenous spread and an increasing number of early lesions being diagnosed, the present trend is toward a more conservative surgical approach to breast cancer in conjunction with adjuvant radiation and, if necessary, chemotherapy or hormonal therapy.

Surgery

Radical mastectomy, as first described in 1894 by Halsted and Meyer, was for many years the standard operation for operable breast cancer. The procedure consists of an en bloc dissection of the entire breast, together with the pectoralis major and minor muscles and the contents of the axilla. At present, breast-conserving surgery is increasingly practiced. Survival rates after conservative surgery are equal to those after radical mastectomy. Although the size of the primary carcinoma is not a limiting factor for breast conservation, if the breast is small, breast conservation is unsatisfactory even for small tumors and is impractical for large tumors.

Routine axillary lymph node dissection has progressively been replaced by lymphatic mapping and sentinel lymph node resection as a less morbid means of determining the tumor status in the axilla. Routine examination of the sentinel node should include hematoxylin and eosin staining. If the node is negative, ultrastaging should be performed, using serial sectioning and immunohistochemical staining for cytokeratin. If the sentinel node is negative, the remaining nodes will be negative with an accuracy of about 95%, so axillary dissection may be avoided. If the node is positive, axillary dissection should be performed.

Breast reconstruction after mastectomy is an integral part of the treatment of breast cancer. It should be available to any woman who desires it, provided that her general condition allows for operation and her expectations for reconstruction are realistic. The procedure may be performed at the time of the mastectomy or may be delayed.

Radiation Therapy

Conservative surgery is always performed in conjunction with radiation therapy to the breast. This approach gives equivalent outcomes to radical mastectomy, and functional and cosmetic results are improved.External-beam therapy is used, with 4500 to 5000 cGy delivered to the entire breast. The ipsilateral supraclavicular and internal mammary nodes may be treated if there are multiple positive axillary nodes. The axilla is not routinely irradiated after an axillary node dissection because of the high incidence of lymphedema.

ADJUVANT THERAPY

Adjuvant systemic therapy is used for most patients with early breast cancer, regardless of lymph node status. Overall, adjuvant therapy reduces the risk for relapse by about one third, and reduces the risk for death by 25%.

Current recommendations for adjuvant chemotherapy and hormonal therapy are as follows:

• Premenopausal patients with estrogen-receptor (ER)-negative tumors should receive adjuvant chemotherapy.

• Premenopausal patients with ER-positive tumors should be considered for hormonal therapy in addition to chemotherapy.

• Postmenopausal patients with ER-positive tumors who have negative nodes should be treated with adjuvant tamoxifen for 2 years followed by an aromatase inhibitor (such as anastrazole) for 3 years or an aromatase inhibitor for 5 years. Those with positive nodes should receive both hormonal therapy and chemotherapy.

• Postmenopausal patients with ER-negative tumors should receive adjuvant chemotherapy.

An added bonus of tamoxifen is a 70% reduction in the risk for cancer in the contralateral breast.

Chemotherapy usually consists of anthracycline-based regimens (e.g., four cycles of doxorubicin [Adriamycin] and cyclophosphamide; six cycles of 5-fluorouracil, doxorubicin, and cyclophosphamide; or six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide), with or without the addition of taxanes (paclitaxel or docetaxel).

In patients with established metastases, symptoms may be palliated with combination chemotherapy. Partial responses are obtained in 40% to 60% of patients, and complete clinical responses are obtained in 5% to 15%. The median duration of response is 5 to 15 months, but responses can last for some years.

Trastuzumab (Herceptin), a humanized monoclonal antibody directed against HER2/neu (human epidermal growth factor receptor 2, also referred to as c-erbB-2), has been approved by the U.S. Food and Drug Administration for patients with early breast cancer in conjunction with chemotherapy and also for the treatment of patients with metastatic breast cancer. Its efficiency is predicted by either HER2/neu protein overexpression or gene amplification.

PROGNOSIS

Although prognosis is related to the stage of the disease and the age of the patient (older patients have a better prognosis), the status of the axillary lymph nodes is the single most important prognosticator. ER status is also of independent prognostic significance; patients with ER-negative tumors have a poorer prognosis.

In the National Surgical Adjuvant Breast Project, patients with negative lymph nodes had an actuarial 5-year survival rate of 83%, compared with 73% for patients with one to three positive nodes, 45% for those with four or more positive nodes, and 28% for those with more than 13 positive nodes.

BREAST CANCER IN PREGNANCY

About 3% of breast cancers occur during pregnancy, complicating about 1 in every 3000 pregnancies. Diagnosis is usually delayed because small masses are more difficult to palpate in hypertrophied breasts. Needle aspiration or open biopsy, however, should be performed promptly on any suspicious mass.

The surgical treatment is essentially the same as for the nonpregnant patient. Postoperative irradiation is delayed until after delivery. For patients with nodal metastases, abortion is advisable in the first trimester of pregnancy because of the teratogenic risks of the adjuvant chemotherapy. Adjuvant chemotherapy can be administered in the second and third trimesters of pregnancy. In the third trimester, chemotherapy should be delayed until after delivery, although surgery should occur promptly after diagnosis.

Stage for stage, prognosis for pregnant patients is not much worse than that for nonpregnant patients. There is no indication to advise against subsequent pregnancy for breast cancer patients who have no evidence of recurrence.

SUGGESTED READING

Bonadonna G., Valagussa P., Veronesi U. Lessons from the initial adjuvant cyclophosphamide, methotrexate, and fluorouracil studies in operable breast cancer. J Clin Oncol. 2008;26:342-344.

Clarke M., Coates A.S., Darby S.C. for the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG): Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: Patient-level meta-analysis of randomised trials. Lancet. 2008;371:29-40.

Del Mastro L., Dozin B., Aitini E., et al. Timing of adjuvant chemotherapy and tamoxifen in women with breast cancer: Findings from two consecutive trials of Gruppo Oncologico-Ovest-Mammel; a Intergruppo (GONO-MIG) Group. Ann Oncol. 2008;19:299-307.

Goldhirsch A., Wood W.C., Gelber R.D., et al. for the 10th St. Gailen Conference: Progress and promise: Highlights of the International Expert Consensus on the Primary Therapy of Early Breast Cancer 2007. Ann Oncol. 2007;18:1133-1144.

Mansel R., Locker G., Fallowfield L., et al. Cost-effectiveness analysis of anastrozole vs tamoxifen in adjuvant therapy for early stage breast cancer in the United Kingdom: The 5-year completed treatment analysis of the ATAC (“Arimidex,” Tamoxifen Alone or in Combination) trial. Br J Cancer. 2007;97:152-161.