Introduction

Fibroepithelial lesions are biphasic neoplasms characterized by a proliferation of stromal and glandular elements, and account for most breast tumors in women under the age of 30, with a peak incidence in the third and fourth decades [31]. Typically presenting as a palpable mass, fibroepithelial lesions represent the spectrum from benign and common fibroadenomas, to benign and rare malignant phyllodes tumors. The imaging characteristics of fibroepithelial lesions are summarized in Table 1.

Table 1 Summary of imaging characteristics of fibroepithelial lesions
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Fibroadenomas

A fibroadenoma is a benign breast tumor that typically presents as a painless, firm, mobile mass. 10 to 25% of the time, patients can present with multiple bilateral masses [7, 11••, 31, 34]. Fibroadenomas arise from the terminal duct lobular unit (or TDLU) and demonstrate a balanced distribution of stromal and epithelial components [11••, 31]. Histologically, they have less cellular stroma and do not demonstrate clefting. The stromal element for fibroadenomas can be fibrous, myxoid, hyalinized, or mixed [11••, 31] Histologic appearance is shown in Fig. 1. On gross specimens, fibroadenomas are ovoid, circumscribed, white, and rubbery masses [7, 31].

Fig. 1
figure 1

Histology slide photograph of a well-encapsulated fibroepithelial lesion with mildly increased stromal cellularity and no stromal atypia (40 × hematoxylin–eosin [H&E] stain), compatible with fibroadenoma

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Given the increased prevalence in younger women, fibroadenoma development is thought to have a hormonal component and tends to regress in women in the post-menopausal state [1, 7, 31]. Further support for a hormonal component for fibroadenomas is seen in an association between men with gynecomastia and fibroadenomas [1, 7, 33]. Other factors thought to play a role in the development of multiple and bilateral fibroadenomas include genetics and certain medications. For example, patients treated with cyclosporine immunosuppressive therapy, such as organ transplant patients, have been shown to have an increased propensity to develop multiple and bilateral fibroadenomas [4, 11••, 31] (Fig. 2). Fibroadenomas can fluctuate in size—one study by Gordon et al. found that fibroadenoma volumes can increase up to 16% per month in women younger than 50 but less than 13% in women over 50 years of age [8]. The acceptable 6-month interval increase in maximum dimension is 20% regardless of age, at which point surgical excision should be performed.

Fig. 2
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34-Year-old status post-renal transplant on immunosuppressive therapy with cyclosporine A. A sequelae of cyclosporine therapy is the spontaneous development of multiple fibroadenomas. At least three oval masses with obscured margins (yellow arrows) in the right breast are seen in this patient (Color figure online)

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Fibroadenoma variants include complex, cellular, myxoid, and juvenile fibroadenomas. Complex fibroadenomas account for approximately 16% of fibroadenomas and demonstrate at least one or more complex features, including epithelial calcifications, papillary apocrine metaplasia, sclerosing adenosis, and cysts larger than 3 mm [1, 31]. Complex fibroadenomas appear to confer an increased relative risk of 3.1–3.7 × for subsequent breast cancer development (as compared to the 1.3–2.1 × relative risk for patients with simple fibroadenoma) [14]. Cellular fibroadenomas have mild to moderately increased stromal cellularity, although there is some subjectivity in this subject without strict criteria. Juvenile fibroadenomas, although typically seen in the adolescent population, have a bimodal distribution with a second peak of incidence in women over 40 years of age [6, 25]. Giant fibroadenomas are a classification that is reserved for lesions greater than 5 cm in size and may show increased cellularity and epithelial hyperplasia (Fig. 3). Given the size of giant fibroadenomas, these lesions can cause breast deformity/asymmetry. The presence of epithelial atypia can suggest that there is an in situ or invasive carcinoma component. Myxoid fibroadenomas demonstrate widespread stromal myxoid changes [5]. In Carney complex patients, which is an autosomal-dominant condition characterized by myxomas, endocrine dysfunction, and skin discoloration, patients develop multiple bilateral myxoid fibroadenomas [31, 34].

Fig. 3
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Post-biopsy mammogram example of a high-density oval mass with circumscribed margins. This was a biopsy-proven giant fibroadenoma, a surgical consultation based on size of the mass was recommended

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Fibroadenomas are often first identified on ultrasound examination, which is the recommended modality for the initial evaluation of palpable breast masses in women under 30 years of age [33, 34]. On ultrasound, fibroadenomas appear as circumscribed oval hypoechoic to isoechoic masses which are parallel to the skin surface with variant posterior acoustic enhancement (Fig. 4). Approximately 2–4% of fibroadenomas contain small cysts on ultrasound, although this is more often seen in phyllodes tumors [35]. Often in older women, fibroadenomas can be associated with coarse “popcorn” calcifications on imaging, which often increase as the fibroadenoma involutes [24, 33, 34] (Fig. 5). On MRI, fibroadenomas commonly present as oval circumscribed T2 hyperintense masses with homogeneous internal enhancement. Approximately 40–60% of fibroadenomas demonstrates non-enhancing internal septations [9, 33, 34].

Fig. 4
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50-Year-old biopsy-proven fibroadenoma. Sonographic features include hypoechoic oval mass with circumscribed margins and parallel orientation. Note posterior acoustic enhancement. Biopsy was recommended based on the fact that the mass was a new and palpable

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Fig. 5
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Characteristic mammographic appearance of an involuting fibroadenoma coarse or “popcorn-like” calcifications. No further imaging or biopsy is needed with this appearance

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Management of fibroadenomas includes active surveillance, surgical resection, or simple dismissal, depending on size and clinical behavior [27]. For example, excision should be considered if there is increased growth of greater than 20% in 6 months as this suggests possible sampling error from a phyllodes tumor. While considered benign, it is important to note that the carcinoma incidence arising from fibroadenomas, though extremely low, is approximately 0.1–0.3% (Fig. 6) [1].

Fig. 6
figure 6

20-Year-old woman with new palpable finding. Age-based ultrasound evaluation demonstrates an oval mass with microlobulated margins. Biopsy was recommended and demonstrates a fibroadenoma with associated low grade ductal carcinomal in situ. Additional mammographic views were obtained and demonstrated no associated calcifications. Patient underwent surgical excision and continues active surveillance

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Phyllodes Tumor

Phyllodes tumors are relatively rare lesions that comprise approximately 2.5% of all fibroepithelial tumors and account for 0.3–1% of all breast tumors in western countries [2, 3]. Unlike fibroadenomas, phyllodes tumors are more often seen in an older age range, occurring predominantly in middle-aged women. The average age at presentation is 40–50 years of age. Interestingly, phyllodes are reported at a higher frequency in Asian women, constituting approximately 7% of breast tumors in this population, and occur at a younger age with an average age of 25–30 years old [15, 20, 35]. In large phyllodes tumors, paraneoplastic syndromes, including hypoglycemia from the secretion of insulin-like growth factor II, have been reported [23].

Pathologically, phyllodes tumors are fibroepithelial neoplasms with epithelium lining hypercellular stroma with leaf-like projections and intervening clefts. They can range from benign to malignant. There are three subdivisions for phyllodes tumors: benign, borderline, and malignant. Most phyllodes tumors are benign, approximately 60–80% [34, 35]. Many histological features help with characterization. Such factors include tumor borders/margin, stromal cellularity, mitotic counts, stromal overgrowth/distribution, stromal atypia, cellular pleomorphism, and malignant heterologous components [16, 26••]. On macroscopic views, phyllodes tumors can appear tan, pink, or gray [31]. The lesions often appear mucoid or fleshy. With larger lesions, areas of hemorrhage or necrosis are possible.

Benign Phyllodes

Clinical features for a benign phyllodes tumor are greater than 20% increase in diameter in a 6-month period [34, 35]. Usually unilateral, phyllodes present as a painless breast mass, not attached to the skin. Multifocality or bilaterality is rarely seen. Patients may occasionally have bloody nipple discharge if there is infarction of the tumor. Phyllodes tumor should be considered in a rapidly enlarging mass in a biopsy-proven or suspected fibroadenoma [28]. The average size of a phyllodes tumor is 4–5 cm, with a larger size of mass increasing the likelihood of a phyllodes tumor [35].

Histological findings for benign phyllodes tumors range along a spectrum. Benign phyllodes appear mildly hypercellular with rare mitoses, usually less than 5–10 per high power field [11••, 31]. There is a uniform stromal distribution with absent or mild stromal pleomorphism and monomorphic spindle cell stromal nuclei (Fig. 7). It is possible to see increased stromal cellularity along the epithelium. Margins are described as pushing or circumscribed with focal areas of stromal overgrowth, resulting in the classic leaf-like architecture [11••, 16, 26••, 31]. There can be occasional small tumor buds protruding into the surrounding tissue. Such protrusions, when left behind after surgery, can act as the nidus for local recurrence thus the importance of wide margin resection. Benign phyllodes are absent of any malignant elements.

Fig. 7
figure 7

Fibroepithelial lesion with leaf-like growth pattern and increased stromal cellularity (20 × H&E stain), compatible with benign phyllodes. (inset) Stroma with minimal to no atypia (100 × H&E stain)

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Imaging alone is not specific enough to distinguish between fibroadenoma and benign phyllodes. On mammography, phyllodes tumors can present as a large oval, round, or irregular dense breast mass with circumscribed or obscured margins. Calcifications are rare. On ultrasound, these tumors appear as large oval circumscribed hypoechoic masses, similar to fibroadenomas (Fig. 8a). The presence of lobulations or indistinct or angular margins increases the likelihood of borderline or malignant phyllodes. Other imaging characteristics of phyllodes tumor on ultrasound are heterogeneous echotexture, posterior acoustic enhancement with or without cystic spaces or internal clefts, and increased vascularity on color Doppler. MRI features for phyllodes include intermediate T2 signal with cystic components and hyperintense fluid in slit-like spaces. The most common internal enhancement pattern is heterogeneous (Fig. 8b). On MRI, phyllodes tumors demonstrate plateau or washout kinetics in 33% of cases, as compared to 22% for fibroadenomas [9, 26••, 34].

Fig. 8
figure 8

a 36-Year-old woman with palpable finding. Ultrasound demonstrates an oval hypoechoic mass with a few angular margins (arrows). Internal echogenicity shows heterogeneous echo patter with the appearance of “cystic-slits”. Biopsy proved a benign phyllodes tumor. b MRI of known benign phyllodes tumor shows an oval mass with irregular margins and heterogeneous internal enhancement

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The diagnosis of fibroepithelial lesions is usually done through an image-guided core biopsy. A key consideration during the biopsy procedure would be to include the edges/capsule of the mass. In most cases, there is good agreement between core needle biopsy and excisional pathology. However, as the tissue samples only constitute a small proportion of the whole tumor, an accurate distinction can be difficult due to limited sampling, tumor heterogeneity, and the degree of histological overlap. For instance, in both fibroadenomas and phyllodes tumors, there may be cellular stromal fragments which can contribute to diagnostic ambiguity. Furthermore, there is no universal strict criterion for distinctly separating degrees of cellularity, which unavoidably introduces subjectivity on the part of reviewing pathologists. There can be an upstaging of fibroepithelial lesions diagnosed on core needle biopsy to phyllodes in 18–42% of cases [13]. As such, a balance needs to be struck between overzealous overcall based on minor histological changes and maximizing sensitivity for correct diagnosis for fibroepithelial lesions. Lastly, careful clinical and radiologic correlation is helpful for correct diagnosis and treatment planning.

Classic management for benign phyllodes is with wide local surgical excision for curative intent. The desired margin is debated within the current literature but most studies state within 1–2 cm [18, 29, 30••, 32]. Benign phyllodes can be shelled out due to their normally defined margins. However, even with negative margins, there is a 2–5% risk of recurrence, usually within 2 years (Fig. 9). Recently, there is a trend toward surveillance if the surgery demonstrates positive margins rather than immediate re-excision [29, 30••]. For exceptionally large tumors, mastectomies can be considered. Although axillary lymphadenopathy is often present, nodal metastasis is rare in phyllodes and so, in contrast to breast cancers, there is no need for axillary lymph node biopsy or adjuvant therapy [18, 35]. Overall, benign phyllodes have a particularly good prognosis with less than 1% incidence of metastasis and mortality of less than 0.3% [35].

Fig. 9
figure 9

40-year-old status post-resection of a benign phyllodes tumor. Follow-up ultrasound demonstrates a recurrence at the lumpectomy site following wide local resection. An irregular hypoechoic mass with irregular margins and associated posterior acoustic enhancement was biopsy-proven recurrence

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Borderline Tumors

Borderline phyllodes comprise approximately 15–20% of phyllodes tumors [11••, 31]. Upon histologic evaluation, borderline phyllodes are diagnosed when the tumor does not meet all the features required for malignant phyllodes. For example, borderline tumors can demonstrate moderate stromal hypercellularity, 5–9 mitoses per high power field, and can demonstrate focally invasive margins [11••, 31] (Fig. 10).

Fig. 10
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Fibroepithelial lesion with leaf-like growth pattern, focal stromal overgrowth, and increased stromal cellularity (40 × H&E stain), compatible with borderline phyllodes. (inset) Moderate stromal atypia with identified mitotic figures

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It is difficult to differentiate between borderline phyllodes and benign phyllodes solely based on imaging features (Fig. 11a). For example, both benign and borderline phyllodes tumors may demonstrate irregular margins on imaging (Fig. 11b). Both can demonstrate increased cystic spaces and increased vascularity. On MRI, borderline phyllodes can demonstrate restricted diffusion, peritumoral edema, and hemorrhage [34, 35].

Fig. 11
figure 11

a 36-year-old with a palpable mass (arrow at metalic marker). Mammogram shows a high-density oval mass with partially obscured margins in the left 2 o’clock position, this was biopsy-proven borderline phyllodes. b Ultrasound of same patient shows an irregular hypoechoic mass with microlobulated margins, corresponding to borderline phyllodes

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Treatment for borderline phyllodes tumors consists of surgical management with possible adjuvant therapy. As in benign tumors, wide surgical excision, or in extreme cases, mastectomy can be performed. Some conflicting literature reports are suggesting possible benefits to radiation therapy or chemotherapy. For instance, the usefulness of radiation therapy in cases of increased risk for local recurrences, such as large tumor burden, uncertain/positive margins, or recurrent disease, has been described [19, 36]. Although radiation therapy can decrease local recurrence, there are no reports showing survival benefit [19, 36]. Currently, consensus does not support endocrine therapy.

Unlike benign phyllodes, borderline phyllodes have a slightly worse prognosis. The 10-year survival rate is 93.4% and distant metastasis is seen in approximately 2% of cases [31, 35]. Additionally, hematogenous metastasis is possible, most often to the lungs and bone. Staging with contrast-enhanced CTs and bone scans are recommended [18,19,20].

Malignant Phyllodes

Malignant tumors are seen in 10–20% of all phyllodes tumors. These are reported more frequently in Hispanic women, particularly those from Central and South America [15, 31, 35]. Malignant tumors usually occur 2–5 years later than benign phyllodes tumors and have higher frequencies of local recurrence (12–65%) and metastases (17–27%) [35].

On pathology, there is marked stromal hypercellularity, stromal overgrowth, which is defined as the absence of epithelial elements in 1 low-power field, and atypia. Per WHO criteria, there is greater than 10 mitoses per high power field [11••, 31]. Malignant phyllodes can be diagnosed in the presence of malignant heterologous elements, such as liposarcoma or osteosarcoma, even in the absence of other WHO features [12, 26••] (Fig. 12). The tumor margins can be invasive, necessitating wide margins to prevent recurrence. Certain markers expressed on immunohistochemistry stains including p53, Ki67, CD 34, and VEGF can help differentiate between cellular fibroadenoma and phyllodes tumors, although of limited use in differentiating between borderline and malignant phyllodes tumors [17, 35]. P53 is a tumor suppression mutation protein, which is a useful marker in correlating with malignancy. Ki67 is a marker for cellular proliferation and is highly expressed in malignant phyllodes. VEGF is an angiogenesis marker and has overexpression in the stroma, resulting in more angiogenesis. CD 34 is expressed in the majority of phyllodes and most stromal cells.

Fig. 12
figure 12

Histological images showed a fibroepithelial lesion with stromal overgrowth, infiltrative borders, marked stromal atypia, and easily identifiable mitotic figures [blue arrows] (100 × H&E stain), compatible with malignant phyllodes tumor. (inset) Heterologous elements such as lipoblasts can be identified (Color figure online)

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On imaging, malignant phyllodes tumors are difficult to differentiate from borderline phyllodes. Clinically, these tumors tend to be large, rapidly expanding masses which can cause breast deformity (Fig. 13a–c). On imaging, malignant phyllodes often appear as circumscribed or irregular masses with irregular margins. Dynamic contrast-enhanced breast MRI typically demonstrates heterogeneous low T1 signal intensity with T2 hyperintense fluid in slit-like spaces [34,35,36]. There may be areas of peritumoral edema or internal hemorrhage (Fig. 13d). Kinetics assessment demonstrates washout in the delayed portions of the curve. Color Doppler interrogation demonstrates increased internal vascularity (Fig. 14).

Fig. 13
figure 13

a Clinical images of a 46-year-old woman with biopsy-proven malignant phyllodes tumor replacing the entire left breast. Ischemia of the skin is present as a sequelae of the large growth of the tumor mass. b Mammographic evaluation in same patient shows a high-density mass with poor compressibility of the breast. The mass again is noted to replace the entire breast. c Dynamic contrast-enhanced breast MR maximum intensity image shows a heterogeneously enhancing mass left breast mass with comparison normal contralateral normal breast. d Non-fat-saturated T1 axial sequences show regions of hemorrhage (arrow) in the left breast mass, in same patient with malignant phyllodes. The patient underwent an emergency mastectomy

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Fig. 14
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38-Year-old woman presenting with a rapidly growing mass. Color Doppler ultrasound shows internal vascularity as an associated feature of the oval mass. This was biopsy-proven malignant phyllodes and after initial attempt at lumpectomy the patient underwent a full mastectomy to achieve negative margins (Color figure online)

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Treatment for malignant phyllodes includes wide local excision or mastectomy. Unlike breast surgery for breast cancers, axillary node sampling is not recommended as there is no disease-free survival benefit. Clinically, lymphadenopathy is noted in 10–15% of patients presenting with malignant phyllodes tumors; however, these tend to be either reactive to tumor necrosis or infected skin ulcerations [34,35,36]. Axillary nodal metastasis is uncommon in malignant phyllodes, seen in less than 1% of cases. Standard practices for surgical margin are typically 10 mm. Recent literature suggests that negative margins less than 10 mm may be adequate without a significant difference in local recurrence [29]. Total mastectomy is generally reserved for situations where the tumor is too large to undergo wide local excision to achieve oncologic control or good cosmetic result. Adjuvant therapy with radiation therapy has been shown to have a reduction in local recurrence rate. Choi et. al. showed that there was an 18% recurrence rate with breast conservation therapy alone vs 3% recurrence rate with combined treatment of breast conservation with adjuvant radiation treatment [36]. Chemotherapy is considered in metastatic disease; in these cases, regimens for soft tissue sarcomas are utilized [34,35,, 35].

Differential Considerations

Differential diagnoses for fibroepithelial lesions are broad, depending on the spectrum of the lesion involved. Table 2 summarizes differential considerations for fibroepithelial lesions. Based on imaging appearance, the differential diagnosis for fibroadenoma include mammary hamartoma, fibroadenomatoid change, tubular adenoma, apocrine adenoma, and nodular pseudoangiomatous stromal hyperplasia [21••, 22••, 24]. Fibroadenomas with lipomatous metaplasia can have overlapping histological features of mammary hamartomas [10]. Some myxoid fibroadenomas can mimic mucinous carcinomas on pathology. And, as mentioned earlier, cellular fibroadenomas can be difficult to distinguish from benign phyllodes tumors both by radiology and by pathology. Circumscribed cancers (papillary, medullary, and mucinous breast cancers) are also included in the differential for all fibroepithelial lesions.

Table 2 Differential diagnoses for fibroepithelial lesions
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For benign phyllodes, differential considerations include periductal stromal tumor (PST) and fibromatosis. Periductal stromal tumor represents an entity that overlaps histologically with phyllodes but tends to be non-circumscribed [31]. Periductal stromal tumors demonstrate spindle cell proliferation localized around the open tubules. The main difference between phyllodes and PST is the absence of leaf-like processes for periductal stromal tumors. However, periductal stromal tumors can progress to phyllodes so these lesions are suspected to be part of the spectrum of disease. Similarly, fibromatosis is composed of bland spindle cells with rare mitoses, which can overlap histologically with benign phyllodes [31]. Lastly, for malignant phyllodes, differential diagnoses include metaplastic carcinoma and sarcoma. Metaplastic carcinoma is more common than malignant phyllodes tumors and must be excluded by core biopsy.

Conclusion

Fibroepithelial lesions are a spectrum from benign to malignant lesions and present a diagnostic challenge for radiologists and pathologists. Unfortunately, the imaging features of many fibroepithelial lesions appear similar on mammography, ultrasound, and MRI [24]. The histological analysis must be carefully combined with clinical and radiological findings to improve diagnostic accuracy. Phyllodes tumors must be considered if there is a rapidly enlarging mass with greater than 20% increase in diameter in 6 months, if the mass size is greater than 3 cm, or when core biopsy pathology results are cellular fibroadenoma, particularly in patients greater than the age of 40. The differential diagnosis for fibroepithelial lesions remains broad and the diagnostician should be familiar with the many entities within the differential.