Fibroepithelial tumors are biphasic tumors characterized by both epithelial (ductal) and mesenchymal (stromal) components and consist predominantly of fibroadenoma and phyllodes tumor. Fibroadenoma is more commonly seen in adolescent or young adult women, but may be seen in older or postmenopausal women as well. The stromal component of fibroadenoma can be highly collagenized, myxoid or cellular, but generally appears homogenous in any given case. In older women, the stroma may be sclerotic and calcified. The stromal component typically compresses the ducts to slit-like “intracanalicular” structures or open and rounded “pericanalicular” structures. There is no evidence that these patterns have biological significance.

Fibroadenomas are generally mobile lesions with smooth, well circumscribed borders on physical examination. However, they may also present as nodular densities or calcified lesions on breast imaging. Fibroadenomas are benign tumors and excision is usually curative. Rarely incomplete excision of a fibroadenoma may be followed by recurrence. Diagnosis of fibroadenoma on core needle biopsy usually is straightforward because of the classic appearance of a biphasic tumor with an intracanalicular or less likely pericanalicular patterns (Fig. 2.2). If the edge of the fibroadenoma is present in the core biopsy, there is a distinct tissue plane (circumscribed) between the lesion and the adjacent normal breast tissue; in the event that the lesional tissue appears to be infiltrating the adjacent breast or adipose tissue, the possibility of phyllodes tumor should be entertained. Fibrocystic changes including papillary apocrine metaplasia, sclerosing adenosis, cystic spaces and epithelial calcifications may be present within the lesion (Fig. 2.3). Sometimes the term “complex fibroadenoma” is applied to fibroadenomas having these changes [10]. The ductal epithelium of a fibroadenoma in the majority of cases is completely benign. However there are exceptions, and the pathologist must evaluate the epithelium of a fibroadenoma with the same criteria used in any breast biopsy. Rarely, atypical hyperplasia or ductal or lobular carcinoma in situ may be found within a fibroadenoma (Fig. 2.4); even more rarely, invasive carcinoma may be present.

Stromal cellularity and atypia are evaluated in fibroepithelial lesions. While such assessment is somewhat subjective, it has been suggested that the stroma of adjacent uninvolved breast lobules be used to determine degree of cellularity and atypia in a fibroepithelial lesion to minimize subjectivity (Table 2.1). One of the diagnostic difficulties facing pathologists in evaluation of core needle biopsies in fibroepithelial lesions is interpretations of lesions with apparently increased stromal cellularity. Young women may have fibroadenomas that are more cellular than those found in older women. There is overlap between so-called cellular fibroadenoma and low-grade (histologically benign) phyllodes tumor on core needle biopsy [11–13], and differentiating between these two can be challenging. The major criterion differentiating phyllodes tumor from fibroadenoma is the degree of stromal cellularity and stroma atypia. Table 2.2 highlights some clinical, radiologic, and pathologic features requiring evaluation in fibroepithelial lesions [14–16]. The diagnosis of phyllodes tumor (Fig. 2.5) requires a constellation of features to be present, as no single feature is entirely specific.

In phyllodes tumor, there is increased cellularity with increased stroma cells around ductal epithelium (referred to as periductal condensation/accentuation), but this pattern is not observed in all cases or may not be evident in a core biopsy. Complicating the assessment of stromal cellularity is the variable degree and distribution of cellularity that may exist within a single phyllodes tumor (stromal heterogeneity). The stroma heterogeneity contributes to the difficulty encountered in making a definitive diagnosis or grading of a phyllodes tumor on core needle biopsy [17].

Aside from the degree of cellularity, the presence of increased mitotic activity in the stroma, and stromal cell nuclear atypia, may allow the diagnosis of phyllodes tumor on core needle biopsy. An additional feature that has been noted is the tendency for some phyllodes tumors to fragment on core needle biopsy, a feature related to the exaggerated ductal lumens typically seen in these tumors [11]. While some low-grade (benign) phyllodes tumors can be identified with confidence on core needle biopsy, cases that are equivocal are often called “cellular fibroepithelial lesion (or tumor),” a term intended to convey the uncertainty in excluding phyllodes tumor. High-grade (malignant) phyllodes tumors (Fig. 2.6) have a very high degree of cellularity, marked nuclear atypia, and mitotic activity, and in some cases histologically sarcomatous and heterologous stroma. The diagnosis of high grade phyllodes is usually not challenging on core needle biopsy as long as the epithelial component (in a typical exaggerated intracanalicular pattern) is also present. When the ductal component is not present in the biopsy, the differential diagnosis of high-grade (malignant) phyllodes tumor will include metaplastic carcinoma (mesenchymal type) or the rare stromal sarcoma of the breast, potentially leading to immunohistochemistry work-up. In both metaplastic carcinoma or stromal sarcoma, normal breast ducts may become surrounded or entrapped by the tumor; this should not be mistaken for evidence of a biphasic neoplasm. Metaplastic carcinoma in many cases can be excluded by the absence of diffuse staining with antibodies to cytokeratin; exclusion of stromal sarcoma may require examination of the excised lesion. If a diagnosis of phyllodes tumor is made on core needle biopsy, the lesion should be excised with a margin of normal tissue, since recurrence of incompletely excised phyllodes tumor may occur. Recurrence in low-grade (benign) lesions has been reported in as many as 10–15% compared to 30% or more for malignant cases [15, 17, 18]. Recurrent phyllodes tumors are sometimes higher grade than the original lesion; it is uncertain whether this is due to progression or to heterogeneity in the tumor [15, 19]. Metastases may occur in cases of phyllodes tumors; the majority of these occur in cases of histologically malignant phyllodes tumors, but rarely metastasis of borderline and, even more rarely, of histologically benign phyllodes tumors has been reported [17].

Once diagnosed, a phyllodes tumor is graded (low versus high) or categorized as benign, borderline, or malignant, based on histological parameters. A recent consensus statement outlines the grading scheme: benign phyllodes tumors have minimal nuclear atypia, pushing borders, and four or fewer mitoses per ten high-power fields (hpf); malignant phyllodes tumors have marked stromal cellularity and atypia, infiltrative margins, and ten or more mitoses per ten hpf and usually have areas of stromal overgrowth (stroma without epithelium in at least one 40× microscopic field: 4× objective and 10× eye-piece); borderline phyllodes tumors have features intermediate between benign and malignant [5].

In some cases, definitive classification of a fibroepithelial lesion into fibroadenoma or phyllodes tumor may require examination of surgically excised nodule or mass, which would allow assessment of overall architecture, stromal cellularity, nuclear features, and mitotic activity. In addition to stromal hypercellularity, the typical phyllodes tumor has an exaggerated intracanalicular pattern producing “leaflike” invaginations, a pattern that may not be evident on core needle biopsy.

Fibroepithelial tumors are rare in the male breast because these tumors arise from intralobular stroma; lobules are normally absent or rare in the male breast. Fibroadenomas may however be seen in males taking androgen suppression therapy, estrogen hormonal treatments, or male-to-female transsexual [20–22].

Papillary lesions or neoplasms of the breast consist of a spectrum of entities which include, papillary hyperplasia , juvenile papillomatosis , nipple adenoma (florid papillomatosis of the nipple ), intraductal papilloma, sclerosing papilloma , “atypical papilloma ” (ADH or DCIS involving papilloma), encapsulated papillary carcinoma , solid papillary carcinoma , papillary DCIS, and invasive papillary carcinoma . A comprehensive review [23–26] of these entities is beyond the scope of this text. The approach to interpretation and the pitfalls in the evaluation of selected papillary lesions will be highlighted. Intraductal papillomas (Fig. 2.7a, b) are lesions composed of epithelial proliferations supported by fibrovascular cores (papillary architecture), and confined to a duct; they may be single or multiple. Solitary papillomas usually occur in the large central (subareolar) ducts, while multiple papillomas typically are located in terminal ductal lobular units (TDLU) of the peripheral breast.

Papillomas range in size from microscopic to macroscopic; the larger lesions may be identified on mammography as a density or mass. Papillomas may occasionally be described on ultrasound as a mass that disappears after the first biopsy; this radiologic description may also be associated with apocrine metaplasia. For a partially cystic mass/lesion, it is often prudent to drain the fluid before biopsy of the solid component, if any. Microscopic papillomas almost always are incidental findings in biopsies or excisions performed for other reasons. Occasionally, however, papillomas, even microscopic ones, become sclerosed and calcified and are identified on the basis of mammographic calcifications.

The epithelial component of a papilloma may be nonproliferative or proliferative. The same histologic criteria used to evaluate non-papillary proliferative ductal epithelial lesions are used to assess papillomas. Papillomas may exhibit varying degrees of usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS). The term “atypical papilloma ” is often used for papillomas in which a portion of the epithelial component is consistent with atypical ductal hyperplasia (ADH) or low-grade DCIS (Fig. 2.7c, d). The 2012 WHO categorization of papillomas recommended the use of the terms “papilloma with atypical ductal hyperplasia (ADH)” and “papilloma with ductal carcinoma in situ (DCIS)” instead of atypical papilloma in the context of low-grade lesions. High-grade DCIS in a papilloma is diagnosed as such regardless of the extent of involvement of the papilloma [27]. According to the WHO, papilloma with ADH and papilloma with DCIS are defined as a papilloma with a monotonous population of low-grade cells with architectural and cytologic features of ADH (<3 mm) or DCIS (3 mm or more), respectively [5, 23, 27]. Note that the size or extent cutoff of 3 mm is different from the cutoff used for de novo (i.e., non-papillary) ADH and DCIS which has a cutoff of 2 mm. It must also be pointed out that the current WHO size criteria for ADH and DCIS in papilloma is slightly different from the original criteria proposed by Page et al., whose criteria were: ≤3 mm for ADH in papilloma and >3 mm for DCIS in papilloma [28]. The use of CK5/6, CK14, and estrogen receptor (ER) may be useful in distinguishing ADH from hyperplasia without atypia (or UDH), with ER having strong homogenous positivity in ADH/DCIS in papilloma and heterogeneous positivity or outright negativity in papilloma without atypia; CK5/6 and CK14 have opposite staining pattern to ER-they are positive in UDH in papilloma but negative or weakly positive in ADH/DCIS in papilloma [5, 23, 27]. The management of non-atypical papillary lesions on core needle biopsy is controversial. Risk assessment of association with carcinoma should probably inform the decision to surgically excise or not. For example, a central papilloma is associated with a twofold increase in the risk of subsequent carcinoma [29, 30], which is similar to the risk of de novo UDH [5, 31, 32]. While atypical papilloma (ADH/DCIS in papilloma) is associated with a risk of associated invasive carcinoma ranging from 5 to 7.5 [28, 30]; this is slightly higher than the risk associated with de novo ADH [5, 31, 32]. It is generally accepted that atypical papillomas and papillary DCIS on core needle biopsies should be surgically excised [25]. However, there are ongoing controversies on the management of central papilloma on core needle biopsy [33–39]. We do not subscribe to “a one-size-fits-all approach” and believe that a prudent approach should involve optimal radiologic–pathologic correlation and clinical presentation. For example microscopic papillomas with no evidence of atypia that are completely encompassed in a core needle biopsy, especially in young patients, probably do not need to be excised [39]. On the other hand, central papilloma may need to be excised to ease patient’s symptoms.

Papillomas may undergo sclerosis , with marked alteration of the papillary architecture; epithelial cells that are “pinched off” by the sclerosis may be present in stroma adjacent to the involved duct. Care should be taken not to mistake entrapped epithelium for invasive carcinoma. Clues include the low-power histologic pattern and the cytologic features. Entrapped epithelium usually is directly adjacent to the involved duct within fibroblastic or sclerotic connective tissue. At high magnification, attention to the cytologic features and the presence of myoepithelial cells (identified on H&E or immunohistochemical stain) is helpful in the distinction from invasive carcinoma.