Benign Breast Diseases: Classification, Diagnosis, and Management
Fibroadenoma is the most common lesion of the breast; it occurs in 25% of asymptomatic women. It is usually a disease of early reproductive life; the peak incidence is between the ages of 15 and 35 years. Conventionally regarded as a benign tumor of the breast, fibroadenoma is also thought to represent a group of hyperplastic breast lobules called “aberrations of normal development and involution”. The lesion is a hormone-dependent neoplasm that lactates during pregnancy and involutes along with the rest of the breast in perimenopause. A direct association has been noted between oral contraceptive use before age 20 and the risk of fibroadenoma. The Epstein-Barr virus might play a causative role in the development of this tumor in immunosuppressed patients.
Fibroadenoma presents as a highly mobile, firm, non-tender, and often palpable breast mass. Although most frequently unilateral, in 20% of cases, multiple lesions occur in the same breast or bilaterally. Fibroadenoma develops from the special stroma of the lobule. It has been postulated that the tumor might arise from bcl-2-positive mesenchymal cells in the breast, in a manner similar to that proposed for solitary fibrous tumors.
Macroscopically, the lesion is a well-circumscribed, firm mass, <3 cm in diameter, the cut surface of which appears lobulated and bulging. If the tumor assumes massive proportions (>10 cm), more commonly observed in female adolescents, it is called “giant fibroadenoma.” Microscopically, fibroadenoma consists of a proliferation of epithelial and mesenchymal elements. The stroma proliferates around tubular glands (pericanalicular growth) or compressed cleft-like ducts (intracanalicular growth). Often both types of growth are seen in the same lesion.
Cytogenetic studies have reported chromosomal aberrations in both epithelial and stromal cells, suggesting that the two components may involve neoplastic changes. Phyllodes tumor is a fibroepithelial tumor of the breast with a spectrum of changes. Benign phyllodes tumor is usually difficult to differentiate from fibroadenoma. Hypercellular stroma with cytologic atypia, increased mitoses, and infiltrative margins of the lesion are the most reliable discriminators to separate lesions with recurrence and malignant behavior. In terms of surgical treatment of these tumors, it is important to recognize phyllodes tumor because it should be excised completely with clear margins to obviate any chance of local recurrence. In cases of recurrent disease, mastectomy is often performed.
Approximately 50% of fibroadenomas contain other proliferative changes of breast, such as sclerosing adenosis, adenosis, and duct epithelial hyperplasia. Fibroadenomas that contain these elements are called complex fibroadenomas. Simple fibroadenomas are not associated with any increased risk for subsequent breast cancer. However, women with complex fibroadenomas may have a slightly higher risk for subsequent cancer. The presence of atypia (either ductal or lobular) confined to a fibroadenoma does not lead to a greater risk for long-term breast carcinoma compared with fibroadenomas in general.
Fibroadenomas in older women or in women with a family history of breast cancer have a higher incidence of associated carcinoma. Two studies, which were considered to provide strong evidence of reliability according to El-Wakeel et al., show that the relative risk of developing breast cancer in patients who had surgically excised fibroadenomas increases in the presence of complex features within the fibroadenomas, ductal hyperplasias, or a family history of breast carcinoma (in a first-degree relative). Progressive somatic genetic alterations that are associated with the development of breast cancer have been studied in fibroadenomas. No genetic instabilities, manifested as loss of heterozygosity or microsatellite instability, have been found in any fibroadenoma components regardless of their association with breast cancer or their histologic complexity.
The current management of patients with clinically or radiologically suspected fibroadenoma varies. Some physicians prefer excision for tissue diagnosis, but conservative management will likely replace surgical treatment in the near future, on the basis of the young age of the patient, findings of benign imaging and clinical characteristics, and benign findings on either FNA biopsy or needle core biopsy. Minimally invasive techniques, such as ultrasound-guided cryoablation, seem to be an excellent treatment option for fibroadenoma in women who wish to avoid surgery, or else the lesion may simply be treated with observation and followed up periodically.
Juvenile fibroadenoma is a variant of fibroadenoma that presents between 10 and 18 years of age, usually as a painless, solitary, unilateral mass >5 cm. It can reach up to 15 or 20 cm in dimension, so although it is an entirely benign lesion, surgical removal is recommended.
Lipoma of the breast is a benign, usually solitary tumor composed of mature fat cells. It is occasionally difficult to distinguish lipoma from other conditions clinically, thus causing diagnostic and therapeutic challenges.
Clinically, a lipoma presents as a well-circumscribed, smooth or lobulated mass that is soft and usually nontender. FNA biopsy of these lesions reveals fat cells with or without normal epithelial cells. Usually both mammography and ultrasound scanning give negative results, unless the tumor is large.
If the clinical diagnosis of lipoma is confirmed by either FNA biopsy or core biopsy, and the mammogram and the ultrasonogram show nothing suspicious for malignancy at the site, the patient is normally followed through palpation after 6 months. However, if the diagnosis is not certain or the lesion grows rapidly, the tumor should be surgically removed.
An adenoma is pure epithelial neoplasm of the breast. This lesion is divided into tubular, lactating, apocrine, ductal, and so-called pleomorphic (i.e., benign mixed tumor) adenoma. Except for lactating and tubular adenomas, these lesions are uncommon. Both lactating and tubular adenomas occur during the reproductive ages.
Lactating adenoma is the most prevalent breast mass during pregnancy and puerperium. It presents as a solitary or multiple, discrete, palpable, freely movable breast mass that tends to be small (<3 cm). On gross examination, the lesion is well circumscribed and lobulated. It is characterized by hyperplastic lobules in which proliferated acini are lined by actively secreting cuboidal cells. Lactating adenoma may also develop in ectopic locations, such as the axilla, chest wall, or vulva. Although the tumor may spontaneously involute, surgical removal may be necessary because of the mass effect it produces, and in cases when lactation is not of concern, medical therapy may be given to shrink the tumor. This tumor does not tend to recur locally, and there is no proven malignant potential.
Tubular adenoma (also termed pure adenoma) of the breast presents as a solitary, well-circumscribed, firm mass. It may resemble the appearance of noncalcified fibroadenoma radiographically. Histologically, tightly packed tubular or acinar structures that are very regular in size and shape are seen in a sparsely cellular stroma. Microcalcifications inside dilated acini have been described; numerous tiny, punctuate, and irregular microcalcifications are prominent on mammography and ultrasonography.
Both lactating and tubular adenomas, (the true breast adenomas) can be distinguished from fibroadenoma and nipple adenoma by the presence of scant stroma in the former.
Nipple adenoma, also known as florid papillomatosis of the nipple ducts or erosive adenomatosis, is a benign tumor of the ductal epithelium that often clinically mimics Paget’s disease and pathologically may be misinterpreted as an adenocarcinoma. Typically, nipple adenoma presents as a discrete, palpable tumor of the papilla of the nipple. Erosion of the nipple and nipple discharge are usually seen. Histologically, the tumor is characterized by proliferating ductal structures that invade the surrounding stroma. A double layer of epithelium lines these ductal structures. The presence of keratin cysts and tiny apical snouts are other distinguishing features of the disease. Generally, a biopsy is necessary for diagnosis. Nipple adenoma can be successfully treated by complete excision of the tumor with normal surgical margins. Recurrences of incompletely excised lesions have been documented. Nipple adenoma is considered a benign lesion, but rarely malignant change within or contiguous with nipple adenoma has been defined.
Hamartoma of the breast is an uncommon benign tumor-like nodule, also known as fibroadenolipoma, lipofibroadenoma, or adenolipoma, composed of varying amounts of glandular, adipose, and fibrous tissue. Clinically, hamartoma presents as a discrete, encapsulated, painless mass. Although the pathogenesis of the lesion is not clear, it is thought to result from a dysgenesis rather than a true tumorous process. Some cases have been reported to be related to a genetic defect called Cowden’s disease. The classic mammographic appearance is a circumscribed area consisting of both soft tissue and lipomatous elements, surrounded by a thin radiolucent zone.
On macroscopic examination, hamartomas are typically well-circumscribed lesions with smooth contours. Histologically, the most characteristic appearance is otherwise normal breast and fat tissue distributed in a nodular fashion within a fibrotic stroma that surrounds and extends to between individual lobules and obliterates the usual interlobular specialized loose stroma.
There are some issues that should be taken into consideration when evaluating hamartomas. First, this lesion can be very easily underestimated if the clinical finding of a distinct lump or breast asymmetry and the imaging features are not interpreted thoroughly. Second, the pathologist should always be careful about a coincidental epithelial malignancy occurring in the lesion, and the lesion has a potential problem of recurrence. Third, the lesion should be placed in the differential diagnosis of biphasic breast tumors.
The current management of hamartomas is surgical removal.
Granular Cell Tumor
Granular cell tumor is an uncommon, usually benign neoplasm that originates from Schwann cells of the peripheral nervous system. It is most frequently found in the head and neck region, particularly in the oral cavity. The tumor occurs in the breast in only 5%–6% of cases.
Clinically, granular cell tumor can simulate carcinoma because of its fibrous consistency, fixation to the pectoral fascia, skin retraction, and ulceration. Mammographic and ultrasonographic findings may further increase the suspicion of a malignant lesion.
Grossly, granular cell tumor is generally 3 cm or smaller and appears almost well circumscribed when bisected; in some tumors, however, infiltrative margins suggestive of a malignant lesion may be encountered. Histologically, nests and sheets of polygonal cells with distinct cell borders and abundant granular eosinophilic cytoplasm are characteristic. The S-100 protein immunoreactivity of these cells supports the hypothesis that granular cell tumor derives from Schwann cells.
Although granular cell tumor is mostly benign, there are a few cases in the literature reported as malignant. Features suggestive of malignancy are tumor size (>5 cm), cellular and nuclear pleomorphism, prominent nucleoli, increased mitotic activity, presence of necrosis, and local recurrence.
Wide local excision is the treatment of choice for both benign and malignant granular cell tumors. Complete removal may require inclusion of muscle and other adjacent structures, and histologically it is recommended that the margins be completely free of tumor. Incomplete excision may result in local recurrences. Adjuvant therapy is not given unless the tumor is malignant.