Benign Breast Diseases: Classification, Diagnosis, and Management

Fibrocystic Changes

Fibrocystic changes (FCCs) constitute the most frequent benign disorder of the breast. Such changes generally affect premenopausal women between 20 and 50 years of age. Although many other names have been used to describe this entity over the years, (including fibrocystic disease, cystic mastopathy, chronic cystic disease, mazoplasia, Reclus’s disease), the term “fibrocystic changes” is now preferred, because this process is observed clinically in up to 50% and histologically in 90% of women.

FCCs may be multifocal and bilateral. The most common presenting symptoms are breast pain and tender nodularities in breasts. Although the exact pathogenesis of the entity is not clear, hormonal imbalance, particularly estrogen predominance over progesterone, seems to play an important role in its development. FCCs comprise both cysts (macro and micro) and solid lesions, including adenosis, epithelial hyperplasia with or without atypia, apocrine metaplasia, radial scar, and papilloma. Over the years, it has been one of the major issues to determine whether these lesions are a risk factor for the subsequent development of breast cancer. As the use of mammography and the identification of benign breast diseases become more common, it is crucial to identify women who are at an increased risk for breast cancer. Therefore, it is practical to evaluate FCCs under a classification system first proposed by Dupont and Page, as nonproliferative lesions, proliferative lesions without atypia, and proliferative lesions with atypia (atypical hyperplasia). In various studies, it has been shown that the great majority of breast biopsies (up to 70%) show nonproliferative lesions.

Nonproliferative lesions include cysts, papillary apocrine change, epithelial-related calcifications, mild epithelial hyperplasia, as well as ductal ectasia, nonsclerosing adenosis, and periductal fibrosis. Proliferative lesions without atypia include moderate or florid ductal hyperplasia of the usual type, sclerosing adenosis, radial scar, and intraductal papilloma or papillomatosis. Proliferative lesions with atypia include atypical ductal and lobular hyperplasia. In each of these lesions, the subsequent risk for breast cancer is associated with the histologic appearance of the lesion : compared with the general population, women with nonproliferative lesions on breast biopsy have no elevation in breast cancer risk, whereas women with proliferative disease without atypia and women with atypical ductal or lobular hyperplasia have a greater breast cancer risk, with relative risks ranging from 1.3–1.9 and 3.9–13.0, respectively, according to various studies. Apart from the histologic features, the age at biopsy and the degree of family history of breast cancer are reported to be the major determinants of breast cancer risk after the diagnosis of benign breast disease. According to Hartmann et al., the risk for breast cancer in young women with a diagnosis of atypical epithelial proliferation is twice the risk observed among women over 55 years with a diagnosis of atypical epithelial proliferation. It was also reported, in the same study, that family history of breast cancer is an independent risk factor and that strong family history may increase breast cancer risk even in patients with nonproliferative lesions. Absolute risk, however, for both atypical and nonatypical epithelial proliferations is quite low. More than 80% of patients with a diagnosis of atypical hyperplasia do not develop invasive cancer during their lifetimes.

Cysts are fluid-filled, round or ovoid structures that are found in as many as one third of women between 35 and 50 years old. Although most are subclinical “microcysts,” in about 20%–25% of cases, palpable (gross) cystic change, which generally presents as a simple cyst, is encountered. Cysts cannot reliably be distinguished from solid masses by clinical breast examination or mammography; in these cases, ultrasonography and fine needle aspiration (FNA) cytology, which are highly accurate, are used.

Cysts are derived from the terminal duct lobular unit. In most cysts, the epithelial lining is either flattened or totally absent. In only a small number of cysts, an apocrine epithelial lining is observed. Because gross cysts are not associated with an increased risk of carcinoma development, the current consensus on the management of gross cysts is routine follow-up of the patient, without further therapy.

Complex (or complicated or atypical) cyst is a sonographic diagnosis that is characterized by internal echoes or thin septations, thickened and/or irregular wall, and absent posterior enhancement. They are reported in approximately 5%–5.5% of all breast ultrasound examinations. The malignancy rate of complex cysts, which is 0.3% as described by Venta et al., is lower than that for lesions classified as “probably benign.” These patients can be managed with follow-up imaging studies. However, if the lesion also includes an intracystic mass (intracystic nodule), it should be regarded as “suspicious for neoplasm” and managed as solid lesions. Either a core needle biopsy or surgical biopsy is indicated for these lesions.

Adenosis of the breast is a proliferative lesion that is characterized by an increased number or size of glandular components, mostly involving the lobular units. Various types of adenosis have been described, of which sclerosing adenosis and microglandular adenosis merit detailed description.

Sclerosing adenosis of the breast is defined as a benign lobulocentric lesion of disordered acinar, myoepithelial, and connective tissue elements, which can mimic infiltrating carcinoma both grossly and microscopically. Sclerosing adenosis can manifest as a palpable mass or as a suspicious finding at mammography. It is strongly associated with various proliferative lesions, including epithelial hyperplasias, intraductal or sclerosing papilloma, complex sclerosing lesion, calcification, and apocrine changes. It can coexist with both invasive and in situ cancers. Studies found sclerosing adenosis to be a risk factor for invasive breast cancer apart from its association with other proliferative lesions of the breast.

Microglandular adenosis of the breast is characterized by a proliferation of round, small glands distributed irregularly within dense fibrous and/or adipose tissue. Most of the glandular structures have open lumina in which eosinophilic material is usually seen. The most important histological feature of microglandular adenosis is that it may lack the outer myoepithelial layer seen in other types of adenosis. The lack of myoepithelial layer makes it harder to differentiate microglandular adenosis from tubular carcinoma. However, the presence of basal lamina encircling glandular structures, which can also be shown by laminin or type IV collagen immunohistochemical stains, and the absence of epithelial membrane antigen staining in the luminal epithelial cells distinguish microglandular adenosis from tubular carcinoma.

Although microglandular adenosis is considered benign, there is some evidence of the potential of this lesion to become invasive carcinoma. Microglandular adenosis also has a tendency to recur if not completely excised.

Apocrine (adenomyoepithelial) adenosis, which seems to be a variant of microglandular adenosis, was first described in association with adenomyoepithelioma. It is an apocrine change in deformed lobular units, sclerosing adenosis, radial scars, and complex sclerosing lesions. The term apocrine adenosis is used to describe a wide spectrum of apocrine lesions, and to prevent its inappropriate use, this term has been proposed to describe apocrine changes in the specific underlying lesions.

Tubular adenosis of the breast is another and rare variant of microglandular adenosis that should be distinguished from tubular carcinoma. The presence of an intact myoepithelial layer around the tubules is the most helpful feature

Apocrine metaplasia is characterized by the presence of columnar cells with abundant granular, eosinophilic cytoplasm and luminal cytoplasmic projections or apical snouts. These cells line dilated ducts or can be seen in papillary proliferations. They are more frequently found in younger women. All normal and metaplastic apocrine cells can be stained with gross cystic disease fluid protein 15.

Atypical apocrine metaplasia should be diagnosed only when the nuclei of the apocrine cells display significant cytologic atypia.

Clear cell metaplasia of the breast is a rare lesion. Its significance comes from its morphologic similarity to clear cell carcinoma. However, the similarity of its immunohistochemical staining profile with that of eccrine sweat glands suggests that clear cell metaplasia may in fact represent “eccrine metaplasia”.

Epithelial Hyperplasia
Epithelial hyperplasia (ductal or lobular type) is one of the most challenging FCCs to diagnose properly. Epithelial hyperplasia is the most common form of proliferative breast disease. It can be difficult to distinguish between ductal and lobular hyperplasias. In addition, it can also be difficult to distinguish between usual ductal or lobular hyperplasias and their atypical counterparts-atypical ductal hyperplasia and atypical lobular hyperplasia.

Ductal Lesions
Normally, breast ducts are lined by two layers of low cuboidal cells with specialized luminal borders and basal contractile myoepithelial cells. Any increase in cell number within the ductal space is regarded as epithelial hyperplasia. Further classification is based on the degree and architectural and cytologic features of the proliferating cells. Usual ductal hyperplasia or simple hyperplasia denotes an increased number of cells without architectural distortion or distention of the ductal contour. Usual ductal hyperplasia does not increase the risk for breast cancer. In mild hyperplasia of the usual type, proliferating epithelial cells are a three- to four-cell layer, whereas moderate hyperplasia describes epithelial proliferation more than four cells thick, often with accompanying bridging of the luminal space. In florid hyperplasia, the lumen is distended and may be obliterated. The most important cytologic features of mild, moderate, or florid epithelial hyperplasia are an admixture of cell types (epithelial cells, myoepithelial cells, and metaplastic apocrine cells) and variation in the appearances of epithelial cells and their nuclei.

The term atypical ductal hyperplasia is defined as a type of a ductal hyperplasia that morphologically mimics low-grade ductal carcinoma in situ (DCIS). Characteristically, it has a uniform population of cells. Most lesions of atypical ductal hyperplasia are small and focal. They involve only a portion of a duct or only a few small ducts measuring <2 mm. With the increasing use of mammography, and detection of calcifications, atypical ductal hyperplasias are being diagnosed more frequently. Atypical ductal hyperplasia is a rare condition among patients having biopsies for a palpable mass, seen in 4% of symptomatic benign biopsies. In contrast, 31% of biopsies performed because of microcalcifications show atypical ductal hyperplasia. The significance of this lesion comes from the fact that the patient has an increased risk for invasive breast cancer, which is about four to five times that of the general population, and reaching nearly a tenfold risk if the patient has a first-degree relative with breast cancer. The risk for breast cancer is higher in the ipsilateral breast, but the contralateral breast is also at risk. Women with atypical ductal hyperplasia develop cancer usually within 10–15 years of the diagnosis. The risk for cancer declines after 15 years. The risk for breast cancer in women with atypical ductal hyperplasia is also related to the patient’s menopausal status. Premenopausal women with atypical ductal hyperplasia have a substantially higher risk than postmenopausal women with that diagnosis. Routine follow-up for both breasts is recommended. Therapy options, such as chemoprevention, should be determined on the basis of other risk factors for breast cancer.

Lobular Lesions
Lobular-type epithelial proliferations, both atypical lobular hyperplasia and lobular carcinoma in situ, are collectively termed lobular neoplasia because, unlike ductal lesions, which exhibit heterogeneous morphologic features, the histologic features of lobular type epithelial proliferations are very similar, and the only difference between atypical lobular hyperplasia and lobular carcinoma in situ is the extent and degree of epithelial proliferation. Because both lesions are regarded and managed as a risk factor rather than well-established precursor lesions, lobular neoplasia terminology has gained general acceptance. Lobular neoplasia is a relatively rare breast lesion. It rarely manifests itself clinically. Lobular neoplasia is identified as an incidental finding in biopsies excised for other abnormalities. The frequency of detection depends on the volume of tissue removed during surgery and extent of histological examination. Lobular neoplasia is most prevalent in perimenopausal women. It is a multifocal lesion, and many patients have lesions involving multiple quadrants of the breast. Both atypical lobular hyperplasia and lobular carcinoma in situ increase the risk for the subsequent development of invasive carcinoma, by about fourfold for atypical lobular hyperplasia and tenfold for lobular carcinoma in situ. Although subsequent carcinomas can occur in either breast without a direct relationship to the previous site of biopsy, in a recent retrospective study, Page et al. reported that the development of invasive carcinoma after atypical lobular hyperplasia was three times more likely to arise in the ipsilateral breast than in the opposite breast. Invasive carcinomas may arise 15–20 years after diagnosis. Systemic follow-up and appropriate risk assessment is recommended for patients with lobular neoplasia.

Lobular carcinoma in situ is considered to be a risk marker rather than an obligatory precursor lesion of invasive breast cancer; therefore, in general, it does not warrant surgical therapy. Most women with a diagnosis of lobular carcinoma in situ do not develop invasive breast cancer within their natural lifetimes. The risk for developing invasive cancer appears to be similar in both the ipsilateral and contralateral breasts. Therefore, if one has to choose surgery for lobular carcinoma in situ, the only logical approach would be a bilateral total mastectomy. Because this is an excessively morbid procedure for patients who have a moderate risk associated with the diagnosis of lobular carcinoma in situ, chemoprevention is the preferred approach for these patients. However, if the patient has other risk factors, such as a high-risk family history, prophylactic bilateral mastectomy with or without reconstruction would be a consideration.

Columnar Cell Lesions
Columnar cell lesions of the breast represent a spectrum of lesions that have been encountered with increasing frequency in needle core breast biopsies because these lesions are commonly associated with microcalcifications and detected by mammographic screening. A working classification of these lesions has been proposed by Schnitt and Vincent-Salomon as columnar cell change and columnar cell hyperplasia, each of which may have atypia or not. Ongoing studies on the clinical significance of atypical columnar cell lesions, which are also known as flat epithelial atypia, have shown that the likelihood of local recurrence or progression to invasive breast cancer is exceedingly low. However, based on the foregoing observations, it has been suggested that at least some lesions are probably neoplastic proliferations that may represent either a precursor of low-grade DCIS or even invasive carcinoma, particularly tubular carcinoma.

When an atypical columnar lesion is encountered in a needle core biopsy, excision is suggested to exclude more advanced lesions such as in situ or invasive cancer. On excisional biopsy specimen, a careful histologic search for areas with diagnostic features of in situ or invasive cancer should be performed. Because this lesion has been referred to by several different names in the literature, including blunt duct adenosis, columnar alteration of lobules, hypersecretory hyperplasia with atypia, pretubular hyperplasia, and columnar alteration with prominent snouts and secretions, it is difficult to assess its significance as a risk marker for development of invasive cancer. Without having firm data, close follow-up of the patient with columnar cell changes is recommended at this point.

Radial Scar and Complex Sclerosing Lesion
Radial scars are benign pseudoinfiltrative lesions of uncertain significance. They are characterized by a fibroelastotic core with entrapped ducts, surrounded by radiating ducts and lobules displaying variable epithelial hyperplasia, adenosis, duct ectasia, and papillomatosis. Previously, radial scars were an incidental finding in breast specimens excised for other diagnostic reasons, but their incidence has increased dramatically as a result of population-based screening programs. Some authors have suggested using the term “radial scar” for lesions measuring <1 cm, whereas the term “complex sclerosing lesion” was reserved for lesions measuring 1 cm or larger.

Radial scars may serve as a milieu for the development of atypical epithelial proliferations, including atypical intraductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, and DCIS. Over the years, many authors have studied the biologic significance of radial scars. In a postmortem study by Nielsen et al., these lesions were commonly associated with benign breast diseases, whereas Jacobs et al. found that radial scars were associated with a doubling of the risk for breast cancer, regardless of the type of primary breast disease, and that the risk was even greater in women with larger or multiple radial scars.

The radiographic features of radial scars are nonspecific and may mimic carcinoma. The role of FNA cytology in diagnosis is limited. Recent publications have shown the importance of core needle biopsy of these lesions for diagnosis, but because malignancy cannot be reliably excluded with limited sampling, a spiculated lesion suggestive of radial scar or complex sclerosing lesion at mammography may be excised on the basis of its size and amount of sampling performed by core biopsy.

Intraductal Papilloma and Papillomatosis
Intraductal papilloma is a discrete benign tumor of the epithelium of mammary ducts. It can arise at any point in the ductal system and shows a predilection for the extreme ends of the ductal system: the lactiferous sinuses and the terminal ductules. The central papillomas tend to be solitary, whereas the peripheral ones are usually multiple. Serous or serosanguinous nipple discharge is the presenting symptom in most women. Papillomas are characterized by formation of epithelial fronds that have both the luminal epithelial and the outer myoepithelial cell layers, supported by a fibrovascular stroma. The epithelial component can be subject to a spectrum of morphologic changes ranging from metaplasia to hyperplasia, atypical intraductal hyperplasia, and in situ carcinoma. The risk represented by the occurrence of such abnormalities in an otherwise benign papilloma is currently debated. Central single papillomas have not been considered premalignant or markers of risk when they are not associated with atypia. Two recent studies found significant correlation between the presence of atypical ductal hyperplasia in papillary lesions on core biopsies and the presence of invasive or preinvasive carcinoma of the breast in excisional biopsies. In another clinicopathologic study, MacGrogan and Tavassoli suggested that the recurrence of papillomas is related to the presence of proliferative breast lesions (including usual ductal hyperplasia, atypical ductal hyperplasia, and lobular neoplasia) in the surrounding breast tissue. Epithelial atypia, even to the extent of low-grade DCIS has no known prognostic significance or impact on outcome when it is confined to the central papilloma. Therefore, if atypia is encountered in a papilloma on an excisional biopsy, the surrounding breast tissue should be carefully examined for further follow-up of the patient.

Papillomatosis (multiple papillomas) is defined as a minimum of five clearly separate papillomas within a localized segment of breast tissue, usually in a peripheral or subareolar location. Multiple papillomas are more likely to occur bilaterally, and their probability of having an in situ or invasive carcinoma is higher than with the central papilloma. Therefore, in patients with multiple papillomas on excisional biopsy, thorough sampling of the specimen, as well as diagnostic radiographic imaging of contralateral breast tissue is suggested to rule out malignancy. All the available data suggest that the finding of a solitary, central, benign duct papilloma does not carry any increased risk for subsequent breast cancer, while multiple papillomas may indicate a slightly elevated risk for subsequent breast cancer.

Juvenile papillomatosis of the breast is defined as severe ductal papillomatosis occurring in young women of <30 years old. There are only eight male juvenile papillomatosis cases reported in the literature. This disease is associated with a heightened risk for breast cancer. Because both a family history of breast cancer and an increased risk for breast cancer are associated with the diagnosis of juvenile papillomatosis, long-term follow-up is recommended both for the patient and the family.

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