Overview of benign breast diseases

INTRODUCTION — Benign breast disease represents a spectrum of disorders that come to clinical attention because of patient symptoms (such as breast pain), palpable lesions or other findings on physical examination, or as imaging abnormalities. Following establishment of a benign diagnosis, treatment in general is aimed at symptomatic relief and patient education.

Some benign breast diseases, such as atypical hyperplasia or lobular carcinoma in situ, confer an increase in the patient's future risk of developing breast cancer and should lead to counseling about screening recommendations and risk reduction strategies. These lesions are considered as risk markers, rather than as premalignant lesions, because those cancers that subsequently develop are not necessarily in the area of the atypia and may occur in the contralateral breast.

This topic will review the pathologic classification and treatment of benign breast disorders; proliferative lesions with atypia are discussed in more detail in a separate topic. (See "Atypia and lobular carcinoma in situ: High-risk lesions of the breast".)

The evaluation of women presenting with symptoms related to the breast and the diagnosis of breast disorders are discussed separately. (See "Nipple discharge" and "Breast pain" and "Clinical manifestations, differential diagnosis, and clinical evaluation of a palpable breast mass".)

Neoplastic diseases of the breast are discussed in other topics. (See "Clinical features, diagnosis, and staging of newly diagnosed breast cancer" and "Breast ductal carcinoma in situ: Epidemiology, clinical manifestations, and diagnosis".)

EPIDEMIOLOGY AND RISK FACTORS — The risk of benign breast diseases is associated with age and hormonal factors:

Age — In a retrospective study of over 61,000 Swedish women, hyperplasia without atypia, fibrocystic changes, and fibroadenomas were quite common at younger ages, increasing during the 30s and 40s and then decreasing thereafter (figure 1) [1]. The peak incidence is typically in the mid-40s. The incidence rates for other benign lesions, such as adenosis, papillomas, or nonepithelial tumors, were much lower.

Risk factors — Benign breast diseases are impacted by several risk factors, though heterogenously [1]:

●Obesity is generally associated with a reduced premenopausal risk of benign breast diseases, with the exception of hyperplasia without atypia.

●No association has been reported between the age of menarche and the risk of benign breast diseases, and the impact of irregular menstrual cycles has been inconsistently reported.

●Oral contraceptives are generally protective against benign breast diseases, especially with longer duration of use, whereas hormone replacement increases the risk of benign breast diseases.

●A family history of breast cancer has been associated with an increased risk of benign breast diseases, predominantly at premenopausal ages.

A study of 68,132 postmenopausal women found that recreational physical activity after menopause was associated with a lower risk of having benign proliferative epithelial breast lesions. The risk was reduced by 6 percent for every 5 metabolic equivalent hours/week increase between baseline and year 3 [2].

CLASSIFICATION OF BENIGN BREAST LESIONS — Benign epithelial breast lesions can be classified histologically into three categories: nonproliferative, proliferative without atypia, and atypical hyperplasia. The categorization is based upon the degree of cellular proliferation and atypia [3-12]. (See "Breast development and morphology".)

NONPROLIFERATIVE LESIONS — Nonproliferative epithelial lesions are generally not associated with an increased risk of breast cancer [3]. It should be noted that terms such as fibrocystic changes, fibrocystic disease, chronic cystic mastitis, and mammary dysplasia refer to nonproliferative lesions and are not useful clinically, as they encompass a heterogeneous group of diagnoses [7,13].

The most common nonproliferative breast lesions are breast cysts. Other nonproliferative lesions include galactoceles, papillary apocrine change, epithelial-related calcifications, and mild hyperplasia of the usual type [7]. Apocrine metaplasia (also referred to as a "benign epithelial alteration") is also a nonproliferative change that is secondary to some form of irritation, typically associated with a breast cyst.

Simple breast cysts — Fifty percent of women will experience a noncancerous breast lump at some point in their lives; approximately one-quarter of these lesions are cysts. Breast cysts are fluid-filled, round, or ovoid masses derived from the terminal duct lobular unit. Breast cysts can present as breast masses or as mammographic abnormalities. Cysts are common in women between 35 and 50 years old. Acute enlargement of cysts may cause severe, localized pain of sudden onset. The diagnosis and management of breast cysts is discussed elsewhere. (See "Breast cysts: Clinical manifestations, diagnosis, and management".)

Galactocele — Galactoceles (milk retention cysts) are cystic collections of fluid, usually caused by an obstructed milk duct. These present as soft cystic masses on physical examination. At mammography, galactoceles may appear as indeterminate masses, unless the classic fat-fluid levels are seen. Ultrasound may show a complex mass. The diagnosis can be made based on the clinical history and aspiration, which yields a milky substance [14]. Once the diagnosis is established, excision is not necessary, and there is no increased risk of subsequent breast cancer. (See "Common problems of breastfeeding and weaning".)

Papillary apocrine change — Papillary apocrine change is a proliferation of ductal epithelial cells showing apocrine features, characterized by eosinophilic cytoplasm [7].

Mild hyperplasia of the usual type — Mild hyperplasia of the usual type is an increase in the number of epithelial cells within a duct that is more than two, but not more than four, cells in depth [7]. The epithelial cells do not cross the lumen of the involved space.

PROLIFERATIVE LESIONS WITHOUT ATYPIA — Proliferative lesions without atypia include usual ductal hyperplasia, intraductal papillomas, sclerosing adenosis, radial scars, adenomas, fibroadenomas, and pseudoangiomatous stromal hyperplasia. These lesions can be associated with a small increased risk of developing breast cancer, approximately 1.5 to 2 times that of the general population [4-7,10,11,15-18].

Usual ductal hyperplasia — Ductal hyperplasia without atypia is a pathologic diagnosis, usually found as an incidental finding on biopsy of mammographic abnormalities or breast masses, characterized by an increased number of cells within the ductal space. Although the cells vary in size and shape, they retain the cytological features of benign cells [7,8]. No treatment is needed for ductal hyperplasia. The risk of subsequent breast cancer in women with usual ductal hyperplasia is small, and chemoprevention is not indicated.

Intraductal papillomas — Intraductal papillomas consist of a monotonous array of papillary cells that grow from the wall of a cyst into its lumen. Although they are not concerning in and of themselves, they can harbor areas of atypia or ductal carcinoma in situ (DCIS). Papillomas can occur as solitary or multiple lesions.

Solitary lesions — Solitary intraductal papillomas may be identified as a mass on mammography (image 1), ultrasound (image 2), magnetic resonance imaging (MRI) (image 3), or ductography [19], or they can be found incidentally [20]. Nipple discharge, particularly bloody nipple discharge, is a frequent clinical presentation. (See "Nipple discharge", section on 'Pathologic (suspicious) nipple discharge'.)

●When a core biopsy demonstrates a papilloma with atypical cells, surgical excision is warranted [17,21-26]. Papillary lesions with atypia are upgraded pathologically up to 67 percent of the time [24,27-29]. After excision, if there is no upgrading beyond atypia, a discussion about endocrine therapy for breast cancer prevention is indicated.

●The data surrounding solitary papillomas without evidence of atypia are less clear [30]. Reported rates of upgrade of pure papillary lesions to atypia or malignancy are highly variable, historically ranging from 5 to 20 percent [21,23,26] but trending down to less than 10 percent in the last decade [20,31-35]. Most available data are retrospective, which did not agree on clinical and imaging findings predictive of upgrading at the time of surgery. In a prospective trial by the Translational Breast Cancer Research Consortium (TBCRC) of 116 intraductal papillomas without atypia on core biopsy, excluding discordant findings, the upstage rate on local review was only 1.7 percent [36].

The current American Society of Breast Surgeons guidelines suggest individualizing the decision to excise a papilloma based on such criteria as size, symptoms (eg, palpability or nipple discharge), and breast cancer risk factors [37]. Excision is recommended in cases of atypia, a palpable mass lesion, bloody nipple discharge (primarily for symptomatic relief), and/or pathology-imaging discordance, whereas small incidental benign solitary papillomas without atypia and with imaging concordance may be offered close clinical and imaging follow-up.

Multiple lesions — Diffuse papillomatosis (multiple papillomas) may present as breast masses or nodules on ultrasound or may be the cause of nipple discharge and can be seen on ductography. Diffuse papillomatosis is defined as a minimum of five papillomas within a localized segment of breast tissue and can be definitively managed with excision [23,38,39]. The risk of subsequent breast cancer in women with diffuse papillomatosis is not well defined but may be higher than with solitary papillomas [40,41]. In one retrospective study, the risk for subsequently developing cancer evaluated in a cohort of patients with papillomas (n = 480) was compared with the risk within the general population [21]. The presence of multiple papillomas without atypia was associated with a relative risk (RR) of 3.01 (95% CI 1.10-6.55). In the presence of atypia, the RR was even greater (RR 7.01, 95% CI 1.97-17.97) [21].

Sclerosing adenosis — Sclerosing adenosis is a lobular lesion with increased fibrous tissue and interspersed glandular cells. It can present as a mass or a suspicious finding on mammography [42,43]. The risk of subsequent breast cancer in those with sclerosing adenosis is about twofold that in the general population [44]. Currently, no treatment, chemoprevention, or enhanced screening is recommended for sclerosing adenosis in the absence of atypia.

Radial scars — Radial scars, also called complex sclerosing lesions, are a pathologic diagnosis, usually discovered incidentally when a breast mass or radiologic abnormality is removed or biopsied. Occasionally, radial scars are large enough to be detected on mammography as suspicious spiculated masses, which cannot be reliably differentiated from spiculated carcinomas by imaging alone [45-48]. Radial scars are characterized microscopically by a fibroelastic core with radiating ducts and lobules.

In general, surgical excision is recommended when radial scars or complex sclerosing lesions are diagnosed on core biopsy, based on series showing that 8 to 17 percent of surgical specimens at subsequent excision are positive for malignancy [49-56]. These high upgrade rates have led to the suggestion that these lesions may actually be premalignant lesions, progressing from scar to hyperplasia to carcinoma [57]. This, however, is controversial, and more contemporary series suggest the presence of undiagnosed cancer is much lower, with upgrade rates in the range of 0.6 to 3.6 percent [58-60]. The upgrade rate is even lower with large-volume (eg, vacuum-assisted) needle biopsy. In a meta-analysis of over 3000 patients with radial scars, the upgrade rate after vacuum-assisted biopsy to invasive and in situ cancer was only 0 and 1 percent, respectively [61]. In a study of 50 patients with radial scars who were followed by active surveillance, no patient progressed on interval imaging at 16 months [62].

The current recommendations from the American Society of Breast Surgeons state that most radial scars "should be excised, although imaging follow-up is reasonable for small, image-detected radial scars that are completely removed or well-sampled with large-gauge devices and in the setting of imaging-pathology concordance" [37].

No additional treatment beyond excision is needed for radial scars. The risk of subsequent breast cancer after excision in this population is small, and chemoprevention is not indicated.

Fibroadenomas — Fibroadenomas are the most common benign tumor in the breast, accounting for one-half of all breast biopsies. In 20 percent of cases, multiple fibroadenomas occur in the same breast or bilaterally.

The etiology of fibroadenomas is not known, but a hormonal relationship is likely since they persist during the reproductive years, can increase in size during pregnancy or with estrogen therapy, and usually regress after menopause. They are most commonly found in women between the ages of 15 and 35 years [63].

Fibroadenomas usually present as well-defined, mobile masses on physical examination or as well-defined solid masses on ultrasound. A well-defined solid mass with imaging features consistent with a fibroadenoma [64] can be managed with core biopsy or short-term (three to six months) follow-up with a repeat ultrasound and breast examination [65]. Definitive diagnosis can only be confirmed with a core biopsy or excision.

Although originally classified as nonproliferative lesions, fibroadenomas are now considered proliferative breast lesions [15]. However, it is important to note that the histologic features of the fibroadenoma influence the risk of breast cancer. For the majority of women with simple fibroadenomas, there is no increased risk of developing breast cancer [4-7,15]. The risk of subsequent breast cancer is slightly elevated only if there is associated proliferative disease or if there is a significant family history of breast cancer.

Simple fibroadenomas — Simple fibroadenomas are benign solid tumors containing glandular as well as fibrous tissue. It is not necessary to excise all biopsy-proven simple fibroadenomas. If a biopsy-proven simple fibroadenoma is asymptomatic, then it can be left in place, although some women wish to have the mass excised so that they will not worry further. Disadvantages of excisional surgery include scarring at the incision site, dimpling of the breast from the removal of the tumor, damage to the breast's duct system, and mammographic changes (eg, architectural distortion, skin thickening, increased focal density).

Cryoablation is an alternative to surgical excision of simple fibroadenomas but should only be considered after a core biopsy diagnosis of fibroadenoma has been made [66-70]. A multicenter trial of 50 patients who underwent office-based cryoablation under ultrasound guidance reported that the lesions tended to disappear progressively [67], and 75 percent were not palpable at 12 month follow-up [68]. Transient side effects included ecchymosis, local swelling, and discomfort that lasted as long as a few weeks after treatment. Percutaneous vacuum-assisted ultrasound-guided excision is another alternative to open excision technique for removal of fibroadenomas but may be less effective for lesions >2 cm [71].

If a presumed simple fibroadenoma increases significantly in size or is symptomatic, then excision is mandated to rule out malignant change and confirm the diagnosis [66,67,71]. Rapid growth of a lesion raises the suspicion for a phyllodes tumor. (See "Phyllodes tumors of the breast".)

Complex fibroadenomas — Complex fibroadenomas present as masses on physical examination or as nodules on mammography or ultrasound. However, on pathology, these contain other proliferative changes, such as sclerosing adenosis, duct epithelial hyperplasia, epithelial calcification, or papillary apocrine changes [72]. They are associated with a slightly increased risk of cancer when multicentric proliferative changes are present in the surrounding glandular tissue.

Appropriate management of complex fibroadenomas is controversial. While some believe that complex fibroadenomas warrant complete removal for histologic examination, others suggest that they can be managed conservatively following core biopsy [72]. In one series of 401 fibroadenomas, 63 (15.7 percent) were considered complex. At a mean follow-up of two years, invasive carcinoma was found in only 1 of the 63 patients with complex fibroadenomas; her initial core biopsy had shown atypical lobular hyperplasia (ALH).

There are several factors that increase the suspicion of either phyllodes tumor or future malignancy. These include stromal mitoses, stromal overgrowth, nuclear pleomorphism, fragmentation, adipose tissue infiltration, or other concerns that may be raised by the pathologist. The American Society of Breast Surgeons recommends excision in these cases [37].

Giant fibroadenomas — Giant fibroadenomas refer to histologically typical fibroadenomas over 10 cm in size [7]. Excision is recommended. The primary challenge for the pathologist is to differentiate these from phyllodes tumors. Phyllodes tumors have a more cellular stromal component than fibroadenomas. (See "Phyllodes tumors of the breast".)

Juvenile fibroadenomas — Juvenile fibroadenomas occur in young women between the ages of 10 and 18 years. They may differ in presentation and management from adult fibroadenomas. Juvenile fibroadenoma is discussed elsewhere. (See "Breast masses in children and adolescents", section on 'Fibroadenoma'.)

Adenomas — Adenomas are pure epithelial neoplasms of the breast. They are distinguished from fibroadenomas by their sparse stromal elements. Adenomas are divided into two main groups: tubular and lactating adenomas. Lactating adenomas occur commonly in pregnancy. They are well circumscribed and lobulated. Although they may require excision because of their size, they do not have malignant potential [7,8]. Tubular adenoma is a rare breast benign neoplasm of young premenopausal women [73]. The imaging or cytologic features are not specific; thus, surgical excision is required to reach a diagnosis by histopathologic analysis [74,75].

Pseudoangiomatous stromal hyperplasia — Pseudoangiomatous stromal hyperplasia (PASH) is a benign stromal proliferation that histologically simulates a vascular lesion [7]. PASH may present as a mass or thickening on physical examination. The most common appearance on mammography and ultrasound is a solid, well-defined, noncalcified mass [76].

The characteristic histologic appearance is a pattern of slit-like spaces in the stroma between glandular units [77]. PASH can be confused with mammary angiosarcoma [8,78].

If there are any suspicious features on imaging, interval growth, or associated symptoms, the diagnosis of PASH on a core biopsy should not be accepted as a final diagnosis, and excisional biopsy should be performed. However, in the absence of suspicious imaging characteristics, a diagnosis of PASH at core biopsy is considered sufficient, and surgical excision is not always necessary [79,80]. A 2018 Choosing Wisely campaign also advocated avoiding surgical excision in patients with concordant imaging findings and without symptoms [81]. There is no increased risk of subsequent breast cancer associated with PASH.

PROLIFERATIVE LESIONS WITH ATYPIA — Proliferative lesions with atypia include atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). These lesions are considered high risk because they are associated with an increase in the patient's future risk of developing breast cancer [82]. Flat epithelial atypia (FEA) is also an atypical proliferation, but this lesion does not appear to convey an elevation in risk beyond that of any associated proliferative lesions present.

The diagnosis, pathology, and management of patients with ADH, ALH, LCIS, and FEA are discussed in another topic. (See "Atypia and lobular carcinoma in situ: High-risk lesions of the breast".)

MISCELLANEOUS BENIGN LESIONS OF THE BREAST

Lipoma — Breast lipomas are benign, usually solitary tumors composed of mature fat cells. They do not contain histologic elements of breast tissue. These present as soft, nontender, well-circumscribed masses. Clinically, it is sometimes difficult to distinguish lipomas from other conditions; the diagnosis can be confirmed with a core or excisional biopsy. Core biopsies are somewhat problematic for lipomas as it is difficult to be certain that the diagnosis is concordant, and lipomas should be surgically excised if they cause diagnostic confusion, continue to enlarge, or grow rapidly [8]. For smaller lesions, excisional biopsy is often preferable. There is no increased risk of subsequent breast cancer associated with lipomas.

Fat necrosis — Fat necrosis of the breast is a benign condition that most commonly occurs as the result of breast trauma or surgical intervention. Fat necrosis can be confused with a malignancy on physical examination and may mimic malignancy on imaging studies [83]. It is sometimes necessary to biopsy these lesions to confirm the diagnosis, although experienced radiologists can usually determine that a lesion represents fat necrosis based on mammographic and ultrasound findings such as oil cysts (collections of liquefied fat) [8,84]. Once the diagnosis is established, excision is not necessary, and there is no increased risk of subsequent breast cancer.

Diabetic mastopathy — Diabetic mastopathy is a benign condition that is typically diagnosed in premenopausal (20 to 40 years old) women who have longstanding type 1 diabetes mellitus [85] and associated complications (neuropathy, retinopathy, and nephropathy) [86]. It has also been reported in women with type 2 diabetes and in men [87]. In patients without diabetes, this condition is known as lymphocytic mastitis or lymphocytic mastopathy [85]. Diabetic mastopathy is rare: a 2017 systematic review of 60 studies, mostly case reports, only included 313 patients [85]. The pathogenesis is unknown, but it may represent an autoimmune reaction as the histologic features are similar to those seen in other autoimmune diseases [88].

The typical presentation is suspicious breast masses that are hard, poorly demarcated, and movable, but painless [89]. They can be single or multiple, unilateral or bilateral, and can involve all quadrants of the breast, but not the axilla [90,91].

Both the clinical features and the imaging characteristics of diabetic mastopathy can mimic those of invasive breast cancer [92]. Thus, multiple imaging studies (ultrasound, mammography, magnetic resonance imaging) may be required to differentiate the two [89].

Image-guided core biopsy is recommended for diagnostic confirmation [93]; fine needle biopsy is not feasible, because of the dense fibrosis. Pathology shows dense, keloid-like fibrosis and periductal, lobular, or perivascular lymphocytic infiltration [94-96]. Surgical excision is required if the core biopsy is not conclusive or is not concordant with imaging [97].

Once the diagnosis of diabetic mastopathy is established, excision is not necessary in asymptomatic patients [98]. Surgical excision can be performed in symptomatic patients [85]. With follow-up, additional lesions may occur, or recur after surgical excision [85]. However, there is only one reported case of invasive breast cancer developing in a patient with diabetic mastopathy [99].

Hamartoma — Hamartomas are benign lesions, also known as fibroadenolipomas, lipofibroadenomas, or adenolipomas [100]. Hamartomas have varying amounts of glandular, adipose, and fibrous tissue. They present as discrete, encapsulated, painless masses or are found incidentally on screening mammography.

Hamartomas are generally felt to be very rarely associated with cancer, and when cancer is detected it is typically incidental [101]. Thus, most screening-detected hamartomas can be safely observed [102]. However, because hamartomas do not have specific diagnostic features on a core needle biopsy, symptomatic or discordant hamartomas should be surgically excised [8].

Idiopathic granulomatous mastitis — Idiopathic granulomatous mastitis (IGM) is an inflammatory mass in the breast. The symptoms and imaging findings may be mistaken for nonpuerperal mastitis, a breast abscess, or, most often, carcinoma. Biopsy is necessary to make a diagnosis. IGM is discussed in more detail elsewhere. (See "Nonlactational mastitis in adults".)

Sarcoidosis — Breast symptomatology in sarcoidosis is rare and seen primarily in patients with systemic involvement. Sarcoidosis of the breast presents as firm, hard masses, mimicking carcinoma. The mammographic appearance is also suspicious with irregular, ill-defined, spiculated masses that are solid on ultrasound. Biopsy is needed for confirmation of the diagnosis [103,104]. There is no increased risk of subsequent breast cancer associated with sarcoidosis of the breast. (See "Clinical manifestations and diagnosis of sarcoidosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Evaluation of breast problems".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Common breast problems (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Classification – Benign epithelial breast lesions can be classified into three categories based on histologic findings: nonproliferative, proliferative without atypia, and proliferative with atypia. (See 'Classification of benign breast lesions' above.)

•Nonproliferative lesions – Nonproliferative lesions are not associated with an increased risk of breast cancer. Management is directed at making a definitive diagnosis and providing relief of symptoms. (See 'Nonproliferative lesions' above.)

•Proliferative lesions – Proliferative lesions without atypia can be associated with a small increased risk of subsequent breast cancer. Once the diagnosis is established, management is also directed at relieving symptoms. Radial scars, papillomas with atypia, complex fibroadenomas, and any lesion discordant with imaging findings require surgical excision. (See 'Proliferative lesions without atypia' above.)

•Proliferative lesions with atypia – Proliferative lesions with atypia such as atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS) are associated with a substantial increase in risk of subsequent breast cancer. Flat epithelial atypia (FEA) is also an atypical proliferation but does not appear to convey an elevation in cancer risk. The diagnosis and management of these breast lesions are discussed in another topic. (See "Atypia and lobular carcinoma in situ: High-risk lesions of the breast".)