Fibroepithelial Lesions

Krings, Gregor; Chen, Yunn-Yi

doi:10.1007/978-3-031-05532-4_7

Gregor Krings⁴ &
Yunn-Yi Chen⁴

855 Accesses

Abstract

Fibroepithelial tumors of the breast are a heterogeneous group of biphasic neoplasms with stromal and epithelial components and widely variable clinical behavior, ranging from benign and harmless to frankly malignant with risk of death. Fibroadenomas are benign and are the most prevalent fibroepithelial tumors, being commonly encountered in core needle biopsies and excision specimens. Phyllodes tumors are far less common and comprise a spectrum of neoplasms ranging from benign to malignant, with variable recurrence and metastatic risk. Diagnosis and grading of these tumors can be challenging, and clinical management is controversial and evolving. Periductal stromal tumors are rare phyllodes tumor variants. Lastly, mammary hamartomas are benign epithelial and stromal proliferations that may resemble fibroepithelial tumors.

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Fibroepithelial Lesions

Fibroepithelial Lesions of the Breast

Fibroepithelial Lesions

Keywords

Mammary Hamartoma

Overview and Clinical Presentation

Hamartomas are abnormal dysgenetic benign growths of cells and tissue types normally present at that particular site. In the breast, the term hamartoma was introduced by Arrigoni et al. in 1971 and refers to radiologically evident or palpable nodules composed of variable admixtures of fibrous, epithelial, and adipose elements, although chondroid, osseous, and smooth muscle components can be present as well. One or more tissue types may predominate [1,2,3,4,5,6,7,8,9,10,11,12,13,14]. Hamartomas include lesions previously referred to as adenolipomas, lipofibroadenomas, fibroadenolipomas, chondrolipomas, and myoid hamartomas.

The incidence of mammary hamartomas is difficult to determine with accuracy, and reported estimates range from 0.1% to 0.7% in some studies to as high as 4.8% of all benign breast tumors in others [3, 8, 10, 11, 13]. Mammary hamartomas may present at essentially all adult ages , including before and after menopause, and have rarely been identified in adolescence [8, 10, 11, 14, 15]. The mean age at diagnosis ranged from 38 to 50 years in several studies [10, 12,13,14, 16]. Women are primarily affected, but rare myoid hamartomas have been reported in men [17].

Mammary hamartoma may present as a painless, mobile, and soft-to-firm palpable mass, as breast asymmetry, or may be identified incidentally on imaging [4, 8, 10, 12,13,14,15]. The clinical impression is often that of a fibroadenoma (FA) [13]. Hamartomas are almost always solitary, but multiple synchronous or metachronous lesions may rarely be seen [10, 13,14,15]. In one study, 12% of cases had coexistent FAs [14]. An exceedingly rare case of bilateral myoid hamartoma has been reported [18]. Studies have shown a wide size range (from <1 to 24 cm), with a mean of 3.9 cm in larger series [4, 6, 8, 10, 12,13,14,15]. A slightly increased incidence in the left compared to the right breast has been reported by some [11, 13, 14, 19, 20]. In a study by Wahner-Roedler et al., 67% of hamartomas were in the left breast, and 39% were in the upper outer quadrant [14]. Rare cases of hamartomas arising in ectopic mammary tissue of the inguinal region or axilla have been described [21, 22].

Gross and Radiologic Features

The typical mammographic appearance of mammary hamartoma is of a round to ovoid nodule of variable density with well-circumscribed margins and a thin peripheral radiopaque pseudocapsule [8, 13, 14, 23, 24]. The degree of lesional heterogeneity depends on the relative amounts of fibroglandular and adipose tissue, with predominantly fibrous lesions mimicking FA and predominantly fatty lesions mimicking lipoma or fat necrosis [23, 24]. Lobulated densities can be seen within the encapsulated fat, described as “slice of salami” [23,24,25]. The presence of normal breast components within a well-circumscribed mass has been described as a “breast within a breast” sign [26]. A peripheral radiolucent halo may be seen [3, 8, 13, 23]. Lesional margins may in some instances be irregular, indistinct, or obscured [14]. Small non-suspicious calcifications may be noted in some cases [14]. The most common sonographic finding is of a compressible well-encapsulated solid, hypoechoic mass with heterogeneous echogenicity and irregular hyperechoic bands or nodules between hypoechoic areas [13, 23, 27, 28]. The adjacent breast tissue is usually displaced mammographically and sonographically [13]. In a study by Sevim et al., ~15% of lesions revealed a partially irregular border by ultrasound [12]. In another series, 5 of 24 hamartomas were not visible on ultrasound [14]. By magnetic resonance imaging (MRI), hamartomas are well-encapsulated ovoid nodules with dark, smooth, and thin rims and internal heterogenicity, which show heterogeneous gadolinium enhancement [13].

On gross examination, mammary hamartomas are typically surgically enucleated, well-circumscribed, soft-to-firm solid masses and may be lentiform or disc-like [3, 6, 8, 15, 29]. Sharp separation from adjacent breast tissue is often obvious [10]. The nature of the cut surface varies depending on the relative amount and distribution of fibroglandular versus adipose tissue, with fibrous areas being white-tan, firm, and rubbery with a smooth, glistening surface, compared to soft pale yellow fatty areas [3, 6, 8, 15, 29]. The lesions may mimic FA, lipoma, or even normal breast tissue. One of nine hamartomas presenting in adolescent girls studied by Chang et al. was noted to have thin, slit-like spaces, but cleft-like spaces were not seen [15]. Small cysts may be noted.

Microscopic Features

The histologic features of hamartomas are variable, and earlier studies attempted to subclassify these lesions into different subgroups. McGuire and Cohn offered a classification system based on “fibrous,” “fatty,” and “fibrofatty” categories, whereas Jones et al. proposed four groups, namely “encapsulated fibrocystic changes,” “FA with fibrous stroma,” “FA-like,” and “circumscribed adenolipoma” [30, 31]. However, these categories are not clinically relevant and are not recommended.

As a group, hamartomas are well-circumscribed, lobulated, and comprised of some combination of normal breast ducts and lobules with interlobular fibrosis and adipose tissue in variable proportions. They can range from predominantly fibrous and/or hyalinized to mostly fatty with scant fibroepithelial elements (Figs. 7.1 and 7.2). A characteristic feature in many cases is an impression of architectural disorganization. The borders are well-demarcated from the adjacent tissue, often with a compressed fibrous pseudocapsule. It has been suggested that the presence of fibrosis between and within individual lobules which obliterates the usual specialized intralobular mammary stroma is a characteristic feature of most hamartomas [3, 4, 6, 8, 13]. However, this feature is not unique to hamartomas and can be seen in other lesions, such as sclerosing lobular hyperplasia [13]. Stromal cellularity varies from paucicellular to mildly cellular. Benign stromal giant cells have been reported very rarely [3]. Pseudoangiomatous stromal hyperplasia (PASH) is not infrequent and may also involve adjacent breast tissue (Figs. 7.1 and 7.2) [4, 6, 8, 10, 13]. Focal stromal ossification may rarely be seen [13]. Adipose tissue is present to variable degree in most cases [3, 6, 8, 13, 30], although Chang et al. noted no fat in 5 of 9 hamartomas presenting in adolescent girls, with the remainder showing only minimal fat [15]. The epithelium is usually comprised of otherwise unremarkable breast ducts and lobules, which are often disorganized (Fig. 7.1). Lobules may be atrophic or poorly formed. Usual ductal hyperplasia may be seen [4, 8, 13]. Small cysts are not uncommon (up to 32% of cases in one study), and apocrine metaplasia or adenosis may be seen (Figs. 7.1 and 7.2) [4, 8, 10, 13, 15]. In rare cases, the epithelium may be involved by atypical hyperplasia, in situ carcinoma, or invasive carcinoma [13, 32,33,34,35,36,37,38,39,40,41].

Adenolipomas are composed predominantly of circumscribed lobulated adipose tissue with structurally normal but typically disorganized breast ducts and lobules (Fig. 7.3) [42]. As in other hamartomas, a thin peripheral fibrous pseudocapsule is present. The epithelium may form small cysts but is not usually hyperplastic. Adipose tissue is almost always mature, but rare adenolipomas with brown fat (adenohibernomas) have been described [43,44,45].

Myoid hamartomas are often considered to be a rare hamartoma variant [5, 7, 46, 47]. These lesions are characterized by variable amounts of smooth muscle bundles or fascicles admixed with adipose tissue, fibrous stroma, and epithelium (Fig. 7.4) [5, 48, 49]. The smooth muscle cells have eosinophilic cytoplasm with elongated cigar-shaped nuclei, but atypia should be absent [49]. Garfein et al. described the presence of occasional epithelioid cells within myoid hamartomas, which may mimic invasive lobular carcinoma [50]. A rare case of lobular neoplasia arising in myoid hamartoma has been reported [51].

Most chondrolipomas are composed of well-circumscribed lobulated fibroadipose tissue containing islands of benign hyaline cartilage, although a few cases of chondrolipomas with associated mammary ducts and lobules have been reported [2, 52,53,54,55,56]. Although generally considered hamartoma variants, these rare lesions do not strictly fulfill the definition of the term, given that cartilage is not a normal component of the breast.

Immunohistochemistry

Immunohistochemistry plays no role in the diagnosis of mammary hamartomas. Herbert et al. studied 24 hamartomas and found immunopositivity for estrogen and progesterone receptors in both epithelial and stromal cells in all cases, whereas other studies described hormone receptor positivity in epithelial cells only [4, 8, 10]. The stromal cells diffusely express vimentin, CD34 and Bcl-2, as do myofibroblasts in areas of PASH [4, 7]. Smooth muscle cells of myoid hamartomas express smooth muscle actin (SMA), desmin, and calponin, whereas these markers often highlight only scattered stromal cells in hamartomas without morphologically obvious myoid differentiation [4, 7, 8].

Differential Diagnosis

Because hamartomas are comprised of disorganized but histologically “normal” breast elements, diagnosis is often not possible based on histologic features alone on core-needle biopsy (CNB) and requires careful radiologic–pathologic and clinical correlation [13, 57,58,59]. The differential diagnosis may include normal breast tissue or benign fibroglandular changes (Figs. 7.2 and 7.3). The diagnosis is more straightforward in an excision specimen showing a mass lesion with pseudocapsule and the characteristic features of hamartoma.

Hamartomas may mimic FAs both clinically and radiologically, and distinction from FA variants or fibroadenomatous change may be challenging on CNB or even excision specimens. Fortunately, this distinction has no clinical relevance. Recognition of intracanalicular growth favors FA, whereas the presence of lobules can raise consideration of hamartoma. Adipose tissue within a fibroepithelial lesion on CNB can raise consideration of hamartoma versus FA with lipomatous metaplasia, phyllodes tumor (PT), or periductal stromal tumor. Recognized intracanalicular growth favors FA or PT. Significant stromal hypercellularity, stromal atypia, or mitoses would be concerning for PT or periductal stromal tumor. Distinction of hamartomas with PASH from nodular PASH or PASH involving FA may not be possible on CNB.

Diabetic mastopathy can have areas of dense fibrosis similar to what is seen in hamartomas, and both hamartomas and myoid hamartomas may demonstrate epithelioid myofibroblasts [50]. However, hamartomas lack the characteristic periepithelial and perivascular inflammation of diabetic mastopathy. The epithelioid myofibroblasts may also simulate invasive lobular carcinoma, and immunohistochemistry for pancytokeratin may be useful in this context.

Pathogenesis and Risk Factors

The pathogenesis of mammary hamartomas is largely unknown. Classification of myoid hamartomas as hamartomas is disputed by some, as smooth muscle may not be considered a normal constituent of breast tissue. Some consider myoid hamartomas to represent adenosis tumors with leiomyomatous myoid metaplasia of myoepithelial cells [46], whereas others have argued that the smooth muscle cells derive from metaplastic stromal cells, blood vessel walls, or a common stromal progenitor cell capable of divergent differentiation [5, 7, 47, 57, 60, 61].

Panagopoulos et al. identified rearrangement of high mobility group AT-hook 2 (HMGA2) in a myoid hamartoma [62]. Rohen et al. described an aberration at chromosome 12q in an adenolipoma from a 58-year-old woman, and Dietrich et al. described the presence of t(12;16) in one and del(1)(p22) in another adenolipoma [63, 64]. A 6p21 alteration involving the region encoding the HMGA1 chromatin remodeling protein has also been described in a hamartoma with dense hyalinized connective tissue and prominent PASH [65]. Notably, 12q13-15 (encompassing HMGA2) or HMGA1 alterations have been described in various benign mesenchymal tumors, such as lipomas, uterine leiomyomas, pulmonary hamartomas , pleomorphic adenomas, and breast fibroadenomas, suggesting a common role for these loci in these lesions [66,67,68,69,70,71,72].

Mammary hamartomas have been described in patients with Cowden syndrome, an autosomal dominant disorder characterized by mutations in the phosphatase and tensin homolog (PTEN) gene, which predisposes to the development of multiple benign and malignant lesions in the breast, skin, thyroid, and endometrium, among others [73,74,75]. Hamartomas developing in this context may be multiple or bilateral [75, 76]. In a retrospective study of breast lesions identified in 19 women with Cowden Syndrome, 17 (89%) had features suggestive of mammary hamartoma, with 84% and 47% of patients having multiple and bilateral lesions, respectively [75]. However, most mammary hamartomas are not associated with Cowden syndrome, and it is unknown if sporadic lesions harbor PTEN alterations.

Prognosis and Clinical Management

Hamartomas are benign and can be surgically enucleated [77] without risk of recurrence. Reports of rare recurrences have been associated with positive margins in the original excision and likely represent incomplete excision [6, 13, 15, 78].

Fibroadenoma

Overview and Clinical Presentation

FAs are the most common fibroepithelial tumors and the most common benign tumors of the breast. The incidence varies with age and is highest in women less than 30 years old [79]. FAs are the most common breast tumors in adolescents and young women. The true incidence is difficult to define, ranging from 9% to 23% in autopsy series and from 7% to 13% in specialty clinics in this age group [80, 81]. In one study, FAs accounted for 91% of all solid breast masses with confirmed tissue diagnosis in girls younger than 19 years of age [82]. FAs can also present in older age groups. In a large multicenter community-based screening population (Breast Cancer Surveillance Consortium), the overall incidence of FAs in women over 40 years old was 18.5%, with a peak incidence of ~24% at ages 40–49 decreasing to <15% in older age groups [83]. In another study, 20% of benign and 12% of all breast masses in postmenopausal women were FAs, with an overall incidence of 10% of biopsies in this population [84].

FAs usually present as a solitary palpable, mobile, firm, and painless mass, but non-palpable lesions may also be detected by mammography as a mass or calcifications [85,86,87,88]. Infarcted tumors, as can occur during pregnancy or lactation, may be painful [89, 90]. Many FAs are small (often <3 cm), but large tumors up to 20 cm may be encountered, especially in adolescents with juvenile FAs, which may grow rapidly in size and/or cause marked breast distortion, raising clinical concern for PT [79, 91, 92]. FAs exceeding 5 cm in size have been called “giant fibroadenomas” and usually occur as single or multiple lesions in adolescent girls after puberty [93,94,95,96,97]. FAs may affect any region within the breast, although the upper outer quadrant is most common. When present in the axilla, FAs can clinically mimic lymphadenopathy. The left breast is involved slightly more often than the right [79]. Some women (13–16%) may develop multiple or, less commonly, bilateral (synchronous or metachronous) FAs, which is more often associated with a family history or other predisposing conditions, such as cyclosporine use [98,99,100,101,102,103,104,105,106]. FAs may also develop in ectopic mammary-like tissue in the chest wall and vulva [107,108,109,110,111].

Gross and Radiologic Features

On mammography, FAs typically present as round or oval, smooth masses with increased density, which may or may not be associated with coarse calcifications [112]. Alternatively, only coarse calcifications may be seen. An increasing number of non-palpable FAs are being detected by screening mammography [85,86,87,88]. It is not always possible to distinguish FAs from other lesions, including benign cysts, PTs, or invasive carcinoma by mammography [112, 113]. Characteristic ultrasound features of FA include a well-circumscribed round or oval homogeneous and hypoechoic mass with variable acoustic enhancement, which may have lobulations and a smooth, echogenic capsule [114,115,116]. In some cases, irregular borders, lesional heterogeneity, or posterior shadowing may simulate carcinoma [116]. Myxoid FAs may be more likely to simulate invasive mucinous carcinoma on ultrasound due to overlapping features [117]. Kim et al. reported enhanced posterior acoustic shadowing in juvenile FAs compared to conventional FAs [115], and Sanchez et al. reported an increased incidence of internal linear hyperechoic septae in juvenile FAs compared to conventional FAs [82]. Juvenile FAs have also been shown to demonstrate more vascularity by color Doppler than conventional FAs [82, 118]. MRI usually reveals a smooth lobulated mass showing low- or high-signal intensity on T2-weighted images [119]. Radiologic differentiation of FA from PT is often not reliable [119, 120].

The gross appearance of FA is of a well-circumscribed ovoid mass with a smooth, bosselated outer surface. The lesions are often less than 3 cm but show a wide size range, reaching sizes up to 20 cm in some cases [79, 96, 97, 121]. The cut surface is usually tan-gray or white, rubbery, and bulging, in some cases with appreciable lobulations and/or very small slit-like spaces. Variations exist depending on the nature of the stroma. Sclerotic/hyalinized FAs are firmer and white with or without associated calcifications, whereas myxoid FAs are soft and gelatinous or mucoid. Tubular adenomas tend to be more tan-brown and slightly softer than conventional FAs.

Microscopic Features

FAs are well-circumscribed but non-encapsulated, nodular or mass-like biphasic stromal and epithelium proliferations. Two distinct growth patterns may be seen: (1) intracanalicular, in which the stromal proliferation compresses ducts into distorted and elongated curvilinear structures with slit-like lumens or clefts (Fig. 7.5a–e), and (2) pericanalicular, in which the stroma proliferates circumferentially around ducts without epithelial compression and with open lumens (Figs. 7.5f–i). Both patterns may be seen in a given FA (Figs. 7.5j). The growth pattern has no known clinical significance. A pericanalicular pattern is often seen in FAs of children and young women in their second or third decade, including juvenile FAs. In the vast majority of cases, the tumor borders are sharply demarcated from adjacent breast tissue. A poorly defined lesion with histologic features of FA that lacks clearly demarcated borders and blends with surrounding breast parenchyma has been described as fibroadenomatous or fibroadenomatoid change (Fig. 7.6).

The stromal cellularity of conventional FAs is low (Fig. 7.5). The epithelial and stromal elements are generally evenly distributed throughout. Tumors with increased stromal cellularity may be encountered, especially in younger women (Fig. 7.7). These cellular fibroadenomas are defined by focal or diffuse mildly increased stromal cellularity, although evaluation of the degree of stromal cellularity is subjective, and a diagnostic threshold is lacking. Cellular FAs may show overlapping histological features with PTs in CNBs and excisions, especially in lesions with a prominent intracanalicular pattern. The absence of stromal-epithelial heterogeneity in cellular FAs is a useful discriminator in this context (Fig. 7.7d, e), especially in the absence of well-developed features of PTs. Subepithelial stromal accentuation is not seen in FAs, although this can be a subjective feature to evaluate, and some fibroadenomas have compressed intralobular stroma in subepithelial zones that can mimic subepithelial stromal accentuation.

The stroma of FAs is usually composed of bland spindle cells with oval nuclei and variable amounts of collagen (Fig. 7.8a). Some lesions have myxoid stroma, and if comprising the entire lesion, are designated myxoid FAs (Fig. 7.8b). Myxoid FAs are commonly multicentric or bilateral in patients with Carney complex but are more often solitary if sporadic [122]. In addition to myxoid FAs, myxoid stromal changes were also noted to involve single or small groups of lobules and interlobular stroma in patients with Carney complex [122]. Some FAs are hypocellular with prominent sclerosis and hyalinization of the stroma that may calcify, and may present as coarse calcifications on mammography (Fig. 7.8c). These hyalinized FAs are common in older women and may be long-standing static or regressing tumors. Although most FAs show consistent stromal composition and appearance throughout, lesions with differing stromal composition may be encountered (Fig. 7.8d, e). PASH was identified in ~4% of FAs in one series [123]. Rare FAs may show benign stromal heterologous elements. Lipomatous metaplasia is seen most commonly, but myoid and cartilaginous metaplasia have also been described (Fig. 7.9). Rare ossification has been reported, predominantly in hyalinized FAs [124, 125].

Stromal mitotic activity is generally absent in conventional FAs, but cellular and juvenile FAs may have increased mitotic activity, especially in younger patients. The degree of mitotic activity overlaps with benign PTs, and an upper limit for mitotic activity within FAs in adults has not been established. Up to 2 mitotic figures/10 high-power fields (HPF) has been suggested to be acceptable in the proper histologic and clinicopathologic context [126,127,128]. The presence of mitotic activity in fibroepithelial tumors presenting in older women should prompt careful evaluation for the alternate diagnosis of PT. Excision should be considered for fibroepithelial tumors with mitoses in CNBs to exclude PT.

Benign multinucleated stromal giant cells may be encountered in fibroepithelial tumors, including FAs, although this is relatively rare (Fig. 7.8f, g) [129,130,131,132,133,134,135,136,137]. These cells have variable amounts of eosinophilic cytoplasm and enlarged, hyperchromatic nuclei, which may be pleomorphic. A floret pattern with multiple nuclei may be seen [46, 131, 135]. The chromatin is fine and smudgy with degenerative features, and nucleoli are either absent or inconspicuous. Nuclear inclusions may be seen. Cell size is variable but may be enlarged in some cases [131]. The giant cells often cluster without significantly increasing the degree of stromal cellularity. Mitotic activity is usually absent, but some studies have reported occasional mitoses [131, 137]. Although the cytologic features may be striking, these cells are of no known clinical significance. Benignity is supported by degenerative nuclear features similar to those found in benign giant cells of other organs (nasal polyps, bladder, gynecologic organs, anus), lack of evidence of recurrence in reported lesions, and lack of correlation with fibroadenoma versus phyllodes histology [129, 131, 135, 138]. The presence of multinucleated stromal giant cells in a fibroepithelial tumor with features of FA should not be used as evidence for PT.

Usual ductal hyperplasia, often with micropapillary or fenestrated architecture, can be seen in the epithelial component of FAs (Fig. 7.10c). In one series, usual ductal hyperplasia was found in ~44% of FAs [123]. Apocrine or uncommonly squamous metaplasia may be seen [123]. Atypical epithelial proliferations are uncommon and include atypical ductal or lobular hyperplasia and ductal or lobular carcinoma in situ (Fig. 7.10d–h) [123, 139,140,141,142,143,144,145,146]. The reported incidence of carcinoma involving FA ranges from 0.01% to 0.3% in screened populations, with the vast predominance being in situ carcinomas [139, 142, 144]. The mean age of patients with associated carcinoma is 42–52 years, approximately 15–20 years older than patients presenting with FAs lacking carcinoma [123, 142, 145]. Whereas some studies reported a predominance of lobular carcinoma in situ, others have shown approximately equal incidence of ductal and lobular carcinoma in situ [123, 142, 145]. In situ carcinoma may also involve ducts adjacent to FAs with carcinoma [123, 142]. Atypical hyperplasia is less common, and flat epithelial atypia may also be seen [123]. Tangential sectioning of elongated non-atypical ducts may sometimes give a false impression of cribriforming (Fig. 7.10i).

FAs arising in children often have features that may otherwise be concerning for PT, such as increased stromal cellularity (mild to moderate) and focal stromal frond formation (Fig. 7.11), but these were not found to correlate with recurrence [147]. Stromal mitotic activity may also be increased beyond what is accepted for FA in adults (up to 7/10 HPF reported) [148]. These features should not necessarily point to a diagnosis of PT in this population in the absence of other diagnostic features.

Complex FAs are defined by the presence of sclerosing adenosis, papillary apocrine metaplasia, cysts greater than 3 mm in size, or epithelial calcifications (Fig. 7.12) [123, 149, 150]. In a large study, the presence of cysts was the single most common histologic feature of these lesions (~29%), with two or more of the features present in ~35% of cases [149]. Another series demonstrated sclerosing adenosis as the most common complex feature (~57%) [150]. Complex FAs occur in older patients (mean age of 35–47 years) and tend to be smaller than FAs without complex features, averaging approximately one-half the size (1.3 ± 0.57 cm) of conventional fibroadenomas (2.55 ± 1.44 cm) in one study [123, 150]. Proliferative epithelium has been noted to occur more often adjacent to complex versus non-complex FAs [149].

Juvenile FAs are more common in adolescents and women younger than 20 years of age, but the prevalence is bimodal, with a second peak in women >40 years old. Conventional FAs are more common than juvenile FAs even in adolescents and younger women [91, 151, 152]. Juvenile FAs demonstrate a mild to moderate increase in stromal cellularity and a pericanalicular or mixed growth pattern, typically with usual ductal hyperplasia. Hyperplasia is often micropapillary and in such cases has been referred to as “gynecomastoid hyperplasia,” based on the resemblance to epithelial hyperplasia in gynecomastia. Stromal cellularity is evenly distributed throughout the lesion, although mild intralesional heterogeneity may occasionally be seen (Fig. 7.13). There is no stromal cytologic atypia. Mitotic activity may be present, especially in adolescents and younger women.

Tubular adenomas are characterized by an adenosis-like proliferation of closely packed rounded ductules with small lumina and little intervening stroma. These lesions are considered FA variants in which the epithelial proliferation has overtaken the stroma and is the dominant component. The ductules often have luminal eosinophilic secretions. Associated lymphocytic inflammation may be present in some cases (Fig. 7.14). During pregnancy or lactation, the epithelium of FAs or tubular adenomas may show focal or diffuse lactational/secretory changes, characterized by bubbly vacuolated cytoplasm, mildly increased nuclear size and hyperchromasia and/or nuclear hobnailing, as well as variable ductular dilatation (Fig. 7.10a, b). In contrast, so-called lactational adenomas (nodular lactational hyperplasia) are likely coalescent lactational lobules.

FAs can infarct in some instances, usually during pregnancy, lactation, or following fine-needle aspiration procedures (Fig. 7.8h). Rare cases of apparently spontaneous infarction have also been reported [89, 90, 153,154,155,156]. The presence of necrosis should therefore not necessarily preclude the diagnosis, although appropriate caution is warranted.

Immunohistochemistry

The stromal cells of FAs have an immunophenotype typical of mammary stroma, including CD34 and SMA positivity [157,158,159], and can express Bcl-2 and aberrant nuclear β-catenin [160,161,162]. Stromal cells in FAs express estrogen receptor (ER)β but not ERα, and this has been correlated with stromal cellularity and young age [163]. The luminal epithelium usually expresses ERα. Progesterone receptor (PR) may be expressed in the epithelium or stroma [164,165,166,167]. Immunohistochemistry plays no role in the distinction of FAs from PTs.

Differential Diagnosis

The diagnosis of conventional FA is often straight forward when typical features are present on CNB or excision. The presence of focal stromal fronds in some FAs can raise consideration of PT, but these are focal and less cellular than those of PTs, without subepithelial stromal accentuation (Fig. 7.15). On CNB, the false negative rate (with respect to PTs) has been estimated to be <1% despite the heterogeneous nature of some PTs [168, 169]. The triple approach of interpreting the pathology results in the context of clinical and radiologic input is suggested to avoid underdiagnosis of PT on CNB. In some cases, prominent hyperplastic epithelium or well-developed PASH may distract from the presence of an underlying FA on CNB. Sclerosing adenosis, cysts, and/or apocrine change within a complex FA may mimic a radial sclerosing lesion on CNB, and vice versa (Fig. 7.12). FAs with lipomatous metaplasia may mimic hamartomas on CNB. Hamartomas tend to have more epithelial-stromal disorganization with intact lobules and lack well-developed intracanalicular or periductal growth patterns. Myxoid FAs can mimic mucinous carcinoma at low power on limited biopsy material. Immunohistochemistry for myoepithelial cells associated with ducts in myxoid FAs may be useful in these cases. Uncommonly, PTs (borderline or malignant) can show paradoxically hypocellular myxoid-appearing stroma, which can be deceptive as the stromal mitoses are only appreciated on higher magnification. Sclerosing lobular hyperplasia (fibroadenomatoid mastopathy) refers to a mass lesion clinically mimicking FA but microscopically showing multiple enlarged lobules with intact architecture and increased numbers of ductules, characteristically associated with collagenized intralobular and sometimes interlobular stroma (Fig. 7.6a, b). Sclerosing lobular hyperplasia is often found adjacent to fibroadenomas and phyllodes tumors [170]. The differential diagnosis of tubular adenomas includes other mass-forming lesions with adenosis, including nodular adenosis, sclerosing intraductal papilloma or ductal adenoma, and sclerosing lobular hyperplasia. The packed ductules of tubular adenomas are round to oval, compared to more irregularly jagged contours in ductal adenoma, and the stroma of tubular adenomas is not hyalinized or sclerotic.

The most challenging differential diagnosis of cellular FA and juvenile FA is with benign PT. The distinction may be difficult in excision specimens and even more problematic in CNBs, where borderline PT could also be considered in the differential. The dilemma is due to overlapping and subjective histopathologic features (degree of stromal atypia, cellularity, and mitoses), limited sampling, and heterogeneity of PTs. For this reason, fibroepithelial tumors with increased stromal cellularity but lacking definitive features of PT, such as marked cellularity, obvious stromal overgrowth, well-developed cellular stromal fronds, obvious periductal stromal condensation, or at least moderate stromal cytologic atypia, are often diagnosed descriptively on CNB, for example, as fibroepithelial neoplasm with cellular stroma. More definitive characterization can be performed on the subsequent excision specimen (see sections “Phyllodes Tumors” and “Differential Diagnosis” for additional discussion).

Pathogenesis and Risk Factors

A role for hormonal influence in FA development and growth is suggested by the increased prevalence of FAs in young premenopausal women, regression or hyalinization with age, and increased risk associated with prior estrogen replacement therapy in postmenopausal women [79, 171, 172]. Women with FAs have also been shown to have elevated plasma estradiol levels compared to a control group and harbor single nucleotide polymorphisms (SNPs) in enzymes involved in estrogen metabolism [173]. The expression of ERβ in stromal cells of FA and the association with younger age and increased stromal cellularity can be interpreted as further support of hormonal influence in tumor development [163]. Additionally, the functional interaction of the Mediator complex, of which subunit 12 (MED12) is recurrently mutated in the majority of FAs, with ER signaling is consistent with this hypothesis [174,175,176] (see section “Molecular Pathology”). Studies analyzing associations of oral contraceptive use with risk of FA development are conflicting, with several but not all studies reporting decreased risk with oral contraceptive use [177,178,179,180,181,182]. Treatment with the selective ER modulator tamoxifen has been associated with decreased proliferative activity of FA stroma [183]. FAs are rare in men and have been associated with hormonal imbalance, such as gynecomastia, exogenous hormone use including estrogen supplementation in male-to-female transexuals, hormone-modulating agents for treatment of prostatic adenocarcinoma, or other drugs such as spironolactone [184,185,186,187]. The occurrence of FAs in men in the absence of such risk factors is extremely rare.

Organ transplant patients immunosuppressed with cyclosporine have an increased risk of developing FAs, which tend to be multiple and bilateral. Cyclosporine-associated FAs have been reported following renal, paired renal-pancreas, and liver transplantation, with intervals between transplantation and presentation of a breast mass ranging from 8 months to 13 years [98, 99, 101,102,103,104, 188, 189]. The average intervals were reported to be 3.5–4.8 years in larger cohorts [99, 103, 190]. Regression has been reported in some cyclosporine-associated FAs after cessation of cyclosporine treatment and replacement with tacrolimus, whereas others remained stable or decreased in size [191].

Myxoid FAs are associated with Carney complex, an autosomal dominant syndrome also associated with myxomas, spotty pigmentation, endocrine hyperactivity, and melanotic schwannomas [122, 192]. These lesions are often multicentric or bilateral [122]. However, the vast majority of myxoid FAs are sporadic.

Molecular Pathology

Early studies of FAs used cytogenetic analysis or comparative genomic hybridization (CGH) to identify karyotypic abnormalities in up to 44% of FAs. Recurrent chromosome level changes were not consistently identified [193, 194]. Additional studies using polymerase chain reaction (PCR)-based or CGH-based approaches found no evidence of monoclonality in either the epithelial or stromal components of most FAs, although some groups identified monoclonal stroma in FAs with either increased stromal cellularity, “phylloid-like stromal expansion, ” or “a phyllodes component” [195,196,197,198,199]. SNP arrays and microsatellite analysis demonstrated only rare loss of heterozygosity (LOH) [200, 201].

More recent DNA sequencing studies have elucidated the genetics of FAs in greater detail and confirm their neoplastic nature. A landmark study by Lim et al. identified recurrent somatic mutations in exon 2 of MED12 in the majority of FAs by whole exome and targeted sequencing [175]. MED12 mutations were subsequently identified across the spectrum of fibroepithelial tumors, including 21–86% of FAs, with most aberrations being missense mutations in codon 44 [202,203,204,205,206,207,208,209,210,211,212]. MED12 mutations were more common in intracanalicular FAs than other growth patterns [206, 208]. Notably, the spectrum of MED12 mutations identified in FAs and PTs (within exon 2 and especially codon 44) is similar to that of uterine leiomyomas, another benign tumor associated with hormonal dysregulation [175, 213,214,215,216]. MED12 exon 2 mutations were also identified in complex fibroadenomas [204, 217], juvenile FAs [204, 218], tubular adenomas [204], and FAs arising in children and adolescents [218, 219], but have not been identified in myxoid FAs [220]. Some studies have reported lower rates of MED12 mutations in juvenile versus conventional FAs, which is consistent with the higher incidence of these mutations in tumors with intracanalicular growth [206, 218]. MED12 mutations were restricted to the stromal component in cases where stroma and epithelium were microdissected and analyzed separately, and mutation status correlated with stromal but not epithelial mRNA and protein expression [175, 206, 217, 221].

MED12, located on the X chromosome, encodes a subunit of the multiprotein transcriptional regulator Mediator complex, which is involved in transcription regulation. MED12, MED13, Cyclin C, and CDK8 or CDK9 comprise a kinase module that interacts with the core Mediator complex to modulate transcriptional activity. MED12 activates the kinase activity of CDK8 through direct interaction of its first 100 amino acids (exons 1 and 2) with Cyclin C. The exon 2 mutations identified in fibroepithelial tumors disrupt this interaction, resulting in global gene expression changes, which may include ER, Wnt, and TGFβ signaling pathways [176]. With regards to ER signaling, MED12 is known to interact with ERα and ERβ [174], and MED12 mutations in FAs were found to correlate with dysregulated ER signaling by gene expression profiling [175]. However, the precise roles of MED12 in the development of fibroepithelial tumors remain to be elucidated.

Other genes are recurrently mutated in FAs at much lower frequencies than MED12. Using a customized 16 gene panel of genes implicated in pathogenesis and progression of fibroepithelial tumors, the most frequently mutated genes in a large international cohort were MED12 (45%), the histone methyl transferase and tumor suppressor KMT2D (15%), and the nuclear hormone receptor RARA (9%), with less frequent mutations in FLNA (6%), TERT (6%), SETD2 (4%), NF1 (4%), PIK3CA (3%), and BCOR (3%) [205]. TERT encodes the catalytic subunit of telomerase transcriptase, and hotspot mutations in TERT promoter have been identified in PTs at high frequency [202, 205, 207, 210, 212, 222, 223]. Some studies have identified TERT promoter mutations in a small number of FAs, while others have not [202, 205, 207, 210, 212, 223]. No TERT promoter mutations were identified in two series of FAs arising in children and adolescents [218, 219], consistent with the benign nature of these tumors, which can sometimes harbor histologic features otherwise raising consideration for PT [147, 148]. Cellular fibroadenomas have been found to have more frequent PIK3CA (9% vs 2%) and MAP3K1 (4% vs 1%) mutations than conventional FAs [207]. There were no significant differences between FAs that recurred, FAs with subsequent ipsilateral recurrence or contralateral occurrence, and FAs without subsequent events, although the few events in this series limit the analysis.

Prognosis and Clinical Management

Risk of Development of Subsequent Carcinoma

The overall relative risk (RR) of developing subsequent carcinoma of the breast appears to be slightly increased (1.5–2.6) in women with a history of FA and is similar to the risk of other benign proliferative breast diseases [149, 224,225,226,227,228]. However, Dupont et al. reported no increased risk of carcinoma in patients with a history of excised FA without complex features in the absence of a family history of breast cancer [149]. Histologic features of FAs and adjacent non-fibroadenomatous tissue affected the RR estimates. Patients with complex FAs or with benign proliferative disease in adjacent breast tissue demonstrated overall RR of developing subsequent carcinoma of 3.1 and 3.47, respectively, and the risk remained elevated for more than 20 years following diagnosis. However, the increased RR associated with complex FAs was 3.72 in the presence of a family history of breast cancer but decreased to 2.6 in women without a family history, which was not significantly different from women with non-complex FAs without a family history (RR 2.06) [149]. More recently, Nassar et al. also described a slightly elevated subsequent breast cancer risk for women with complex FAs (RR 2.27 versus 1.49 for simple FA), but this was ascribed to other concomitant histologic features (proliferative breast disease and incomplete involution). When stratified by these additional factors, complex FA did not result in increased breast cancer risk [229]. In the study by Dupont et al., the RR associated with FAs showing atypical hyperplasia in the adjacent breast was 7.29, which is higher than the accepted RR (4.1–4.5) of atypical hyperplasia in the absence of FA [149, 230]. McDivitt et al. also reported an increased RR of 6.29 in patients with both FA and atypical hyperplasia, although the location of the atypical proliferation within and/or adjacent to the FA was not described [228]. When atypical ductal or lobular hyperplasia is confined to FAs without involvement of adjacent tissue, the risk for developing subsequent carcinoma is not increased relative to that of the FA alone [231].

Clinical Management and Outcomes

In the absence of cellular stroma, mitotic activity, or other atypical features, a diagnosis of FA can usually be made confidently on CNB, especially in conjunction with the triple approach of correlating pathology, radiology, and clinical features. False negativity rates (i.e., incorrect biopsy diagnosis of FA with subsequent diagnosis of PT on excision) have been estimated to be <1%) [169].

Surgical versus non-surgical treatment of conventional FAs diagnosed on CNB depends on patient preference and risk factors. In the absence of epithelial atypia, radiologic–pathologic discordance, or concerning clinical behavior such as rapid growth, observation with conservative clinical follow-up is a reasonable option, and this approach is recommended by the American Society of Breast Surgeons [126, 232, 233]. Fibroepithelial tumors with cellular stroma on CNB are often excised to exclude PT.

For women undergoing surgical excision, solitary FAs can be enucleated, and most FAs do not recur after complete excision. In a survey-based study of adolescents and young adults, fibroadenomas developed at or near the original surgical site in 12% of respondents [234]. Non-surgical therapeutic options include percutaneous vacuum-assisted image-guided biopsy (Mammotome) and cryoablation [235,236,237,238,239,240,241,242,243,244,245]. In one study, the recurrence rate following vacuum-assisted biopsy was 33%, with only lesions >2 cm showing clinical recurrence [236]. In a study by Kaufman et al. with 2.6 years average follow-up, 84% of FAs in women aged 13–66 years were non-palpable following cryoablation, with lesions ≤2 cm showing a better response compared to lesions >2 cm. Ultrasound revealed a median 99% reduction in FA volume with treatment, and smaller lesions resorbed faster than larger lesions [239]. Rare residual palpable FAs have been excised following cryoablation due to patient preference, and these were reported to show necrotic debris without viable lesional tissue or “shrunken hyaline matrix with preserved collagenous architecture” [237, 240, 246].

Studies directly addressing management of complex FAs diagnosed on CNB are scarce. In a study of 20 complex FAs initially diagnosed on CNB, one was reclassified as benign PT on excision, and another with atypical lobular hyperplasia on biopsy was upgraded to invasive lobular carcinoma on excision [150]. Complex FAs are generally managed using the same principles as conventional FA.

Patients with juvenile FAs are not considered to be at increased risk for subsequent development of PTs or carcinoma [91, 151]. Although objective data are limited, most patients with juvenile FAs undergo excision, given the often large and rapidly growing size of these lesions in adolescents and the inability to definitively exclude PT on CNB [247, 248]. Excision should aim to preserve as much breast tissue as possible in adolescent girls in order to allow for proper breast development [91, 247, 249, 250]. Normal breast development can be seen after surgery, even in cases with only limited residual breast tissue remaining after excision [91]. In a study of juvenile FAs in adolescent girls, none of the solitary lesions recurred after local excision with or without a rim of normal adjacent tissue after a mean follow-up period of 3.8 years, whereas all six girls with multiple lesions developed additional lesions within 18 months following initial excision [91].

Excision is generally recommended for FAs with atypical ductal hyperplasia diagnosed on CNB. FAs with associated carcinoma should be managed similar to breast carcinoma in the usual setting [251].

Phyllodes Tumor

Overview and Clinical Presentation

PTs are biphasic epithelial and stromal neoplasms characterized by stromal hypercellularity and often characteristic exaggerated leaf-like intracanalicular architecture, with recurrence and/or metastatic potential, the likelihood of which varies along a spectrum from benign to malignant [252]. Johannes Mueller initially named these lesions cystosarcoma phyllodes in 1838 to reflect their fleshy, leaf-like, and sometimes cystic appearance [253]. However, this term is no longer used, as most PTs are benign, without sarcomatous features or aggressive behavior.

PTs are rare, reported to represent between 0.3% and 1% of all primary breast tumors and 2.5% of fibroepithelial tumors in women of European descent [252]. Because incidence studies are from tertiary care centers, the true incidence is likely to be lower [126]. The relative frequencies of benign, borderline, and malignant PTs are ~60–75%, 15–26%, and 8–20% [252, 254,255,256,257]. The average age at presentation is 40–50 years in most studies, which is 10–20 years older than that of FA [252, 257,258,259,260,261,262,263,264]. A Surveillance Epidemiology and End Results (SEER) study reported a mean age of 50 years for malignant PTs [262]. Although PTs are overall not common in women under 30 years old and are rare before menarche, they may present in essentially any age group, including children [147, 148, 265,266,267,268,269]. Most but not all PTs in children are benign [147, 148, 266,267,268,269,270,271].

PTs are more common in Asian and Latina white women, and these tumors may present at an earlier age [16, 252, 259]. In a study of Asian women of multiple ethnic backgrounds, the overall incidence of PT was 3.8%, and the average age of presentation was 25–30 years, with up to one-third of patients presenting in adolescence [16]. Latina white women born in Mexico, Central or South America have a three- to fourfold increased risk of developing malignant PTs compared to Latina white women born in the United States [259]. Asian women may also be at increased risk of recurrence [254].

PTs are rare in men, in whom they have been associated with gynecomastia, suggesting a role for hormonal imbalance in development [184, 272,273,274,275,276,277]. Consistent with a hormonal role in development, PTs have been reported during pregnancy or following in vitro fertilization in women [278,279,280,281].

PT often presents as a rapidly growing new mass or as rapid growth of a previously stable lesion [263, 264, 282, 283]. Gordon et al. suggested that PTs have a faster detectable growth rate as measured by ultrasound than FAs [284]. The average tumor size is 4–5 cm, but smaller tumors are detected due to screening mammography [254, 257, 258, 260, 263, 273, 285,286,287,288], and giant tumors >30 cm have been reported [289,290,291]. In a large study of 605 PTs, sizes ranged from 0.3 to 25 cm, with an average of 5.2 cm [257]. Malignant tumors can be larger than benign tumors, but there is broad overlap [254, 258, 288, 292]. In a study of 335 PTs, average tumor sizes were 4.3, 8.1, and 9.2 cm for benign, borderline, and malignant PTs, respectively, but ranged from 2 cm or less to more than 20 cm across all tumor grades [288]. Large tumors may cause skin discoloration, thinning, dilated subcutaneous veins, or ulceration [263, 264, 282, 287]. In one study, skin ulceration was found in 3 of 335 cases (all tumors ≥16.5 cm), two of which were malignant and one of which was borderline [288]. Tumors may invade the chest wall [263, 264, 293]. Bloody nipple discharge can occur from spontaneous infarction [294]. The vast majority of PTs are unilateral and clinically unifocal [254, 257, 258, 260, 263, 273, 285,286,287, 293], although satellite nodules may be identified on pathologic examination. Rare bilateral tumors have been reported [258, 263, 286, 288]. The left and right breasts are involved with approximately equal frequency [257, 263, 273, 295, 296]. The most common single site appears to be the upper outer quadrant, but larger tumors more often span multiple quadrants [263, 296]. Although axillary lymphadenopathy is relatively common at presentation (up to 20% of patients), lymph node metastases are very rare [264, 273, 285, 297,298,299,300]. In a SEER study of 1035 PTs, one-quarter of patients had some type of lymphadenectomy and 9% had at least ten lymph nodes removed, but nodal metastases were identified in only nine patients [299]. Rare cases of hypoglycemia associated with PTs have been described [301,302,303,304].

Gross and Radiologic Features

Mammography of PT usually reveals a rounded non-spiculated mass with smooth or lobulated borders and homogenous density [295, 305, 306]. A peripheral halo can be seen in some cases, due to compression of adjacent breast parenchyma [295, 305, 306]. A minority of tumors demonstrates areas of border irregularity, and tumors with loss of margin definition can mimic carcinomas radiologically [305, 306]. Calcifications are rarely identified and can be present in benign or malignant tumors, including tumors with necrosis or osseous differentiation [295]. Internal fat density has also been described in tumors with fatty metaplasia or liposarcoma-like differentiation [295]. By ultrasound, PTs similarly present as well-rounded oval or lobulated masses [305, 307]. Cysts and internal echoes with a heterogeneous pattern are often present [295, 305, 307]. Typical MRI findings of PTs include a round or lobulated mass with well-defined margins and heterogeneous internal structure with internal septations. Reliable distinction of PT from FA or among PT grades is not always possible by mammography, ultrasound, or MRI [120, 295, 305, 307,308,309,310,311]. In one MRI study, up to one-third of PTs (and 23% of FAs) showed contrast enhancement features suspicious for invasive carcinoma [120]. Admietz et al. studied PTs and FAs by real-time elastography and found that PTs often demonstrate an elastic center with a peripheral inelastic rim, which was present in only 5% of FAs [312].

PTs vary in gross appearance, due to tissue heterogeneity within and between tumors. Most tumors are well-circumscribed on gross examination and are often surgically enucleated without definitive preoperative diagnosis [252, 288]. Even tumors with microscopic tissue infiltration are usually macroscopically circumscribed. Smaller satellite nodules may be present at the periphery. The cut surface is usually tan-pink or gray and bulging and may be firm, mucoid, and/or fleshy. A characteristic finding is the presence of a whorled surface with curvilinear clefts and/or cystic spaces. However, smaller lesions may appear more homogenous [252]. Norris and Taylor noted gelatinous or translucent areas in 56% and cystic areas in 33% of tumors in their series [263]. Malignant PTs with extensive stromal overgrowth can appear solid, firm, and fibrous. Adipose metaplasia or liposarcoma-like elements are soft and yellow. Tumors with chondroid or osseous elements may be gritty or show frank cartilage or bone formation. Grossly evident necrosis or hemorrhage can be seen, especially in larger tumors, but is not common [263, 288]. Overlying skin may be ulcerated.

Microscopic Features

Histological Features

PTs are fibroepithelial neoplasms with stromal proliferation resulting in increased stromal cellularity. Classically, these tumors demonstrate an exaggerated intracanalicular growth pattern, with leaf-like stromal fronds surfaced by epithelium that protrude into dilated clefts or cyst-like spaces (Fig. 7.16 and 7.17). Well-developed stromal fronds are bulbous and may have smaller invaginating clefts or notches along their convexity. The stromal proliferation is often more pronounced in the area immediately subjacent to the epithelium, which has been referred to as periepithelial or subepithelial condensation or accentuation [252]. Mitotic activity may be increased in the subepithelial zone (Fig. 7.18). The combination of increased stromal cellularity and leaf-like architecture with or without subepithelial stromal accentuation can be used to distinguish PTs from FAs in classic cases. However, stromal fronds may be focal or absent in some PTs. Some tumors instead have elongated branching, clefted ducts, sometimes with a staghorn-like appearance, embedded within the cellular stroma (Fig. 7.19) [252, 313]. Stromal mitotic activity and atypia are variable and are important parameters for tumor grading. Marked stromal proliferation may give rise to stromal overgrowth, defined as the disproportionate proliferation of stroma with lack of epithelium in at least one low-power microscopic field, i.e., at 40× (4× lens with 10× ocular) magnification [252, 314]. Stromal overgrowth is typical of malignant tumors and may be focally present in some borderline tumors but is not a feature of benign tumors [252, 314, 315]. Although stromal hypercellularity is one of the key features of PTs, cellularity is not infrequently heterogeneous, as is the relative distribution of stroma and epithelium. Stromal heterogeneity includes the presence of FA-like areas in some PTs (Figs. 7.20 and 7.21), and may infrequently lead to underdiagnosis in CNB or fine-needle aspiration biopsies if diagnostic cellular areas are not sampled (see section “Differential Diagnosis”). The stroma can vary from myxoid to hyalinized to more fibrous. Most (~87%) PTs in one large series showed myxoid degeneration [288]. PASH (Fig. 7.22) was described in ~73% of cases in one study, being more common in benign (~76%) compared to borderline (18%) or malignant (~6%) tumors [288]. In a core biopsy, the presence of PASH in a fibroepithelial tumor can raise consideration of PT over a cellular FA, and together with other features, would raise enough suspicion to advocate excisional biopsy for the patient. Multinucleated stromal giant cells may be present [135, 137]. One group reported the presence of stromal giant cells in ~9% of PTs, with increasing numbers correlated with increasing grade [288]. Benign stromal giant cells are typically focal and distinct, with degenerative-type atypia compared to background stromal cells, but distinction from neoplastic tumor cells can sometimes be problematic. In such cases, irregular nuclear borders, lack of degenerative-type chromatin, vesicular chromatin, prominent nucleoli, and especially mitotic figures favor neoplastic atypia (Fig. 7.22). Benign metaplastic stromal changes may be seen but are rare, with one series reporting an incidence of 0.3% each for benign adipose metaplasia and benign chondromyxoid metaplasia (Fig. 7.22) [288]. Heterologous differentiation is most commonly liposarcoma-like, although the presence of liposarcoma within a PT is no longer considered a diagnostic feature of malignancy in the World Health Organization (WHO) classification of breast tumors [252]. Less common malignant heterologous elements, which are by themselves diagnostic of malignancy, include chondrosarcoma, osteosarcoma, and rhabdomyosarcoma (Fig. 7.23) [252, 257]. Mamoon et al. described an exceedingly unusual case of angiosarcoma arising in a recurrent PT [316].

The epithelium consists of bilayered luminal epithelium and myoepithelium. Usual ductal hyperplasia is not uncommon, with approximately 37%, 28%, and 9% of tumors showing mild, moderate, and florid hyperplasia in one study (Fig. 7.24e, f) [288]. Apocrine or squamous metaplasia may be present, the latter of which may line ducts or form squamous cysts (Fig. 7.24a–d) [254, 263, 288, 317]. Calcifications are rare and can be seen in association with epithelium or stroma. Atypical ductal or lobular hyperplasia is rare in PTs, and in situ or invasive ductal or lobular carcinoma is even less common (Fig. 7.24g–n) [318,319,320,321,322,323]. In a large study by Tan et al., only one malignant PT (0.03% of tumors in this series) showed ductal carcinoma in situ (DCIS), five cases (1.5%) showed atypical ductal hyperplasia, and 1 case (0.03%) each showed atypical lobular hyperplasia and lobular carcinoma in situ (LCIS) [288]. PTs of all grades may infarct, but tumor necrosis is far less common and mostly present in malignant tumors (Fig. 7.25) [288]. The ipsilateral or contralateral breast parenchyma may contain FAs or fibroadenomatous change, and some studies have correlated the presence of synchronous ipsilateral FAs or fibroadenomatous change with tumor recurrence [258, 288, 324,325,326,327]. Adjacent satellite PT nodules may also be seen.

Periductal stromal tumors are characterized by concentric stromal proliferations around dilated, non-compressed ducts, with adjacent proliferative nodules coalescing to form a larger mass (Fig. 7.26a–d). Because periductal stroma tumors may recur as PTs, and areas resembling periductal stromal tumor can be seen in some PTs, they are considered PT variants and are classified as a PT subtype in the WHO classification of breast tumors [252, 328]. The term periductal stromal sarcoma was originally used to describe tumors with moderate stromal cell atypia, at least three mitotic figures per 10 HPF, and infiltrative growth, whereas periductal stromal hyperplasia was non-infiltrative with less cytologic atypia and mitotic activity (Fig. 7.26e, f) [328]. Defined as such, 1 of 20 sarcomas recurred locally (and 1 distally), as did 1 of 7 hyperplasias. The term sarcoma is discouraged in lieu of tumor to more accurately reflect the variable but often non-malignant behavior. Associated ducts may show usual ductal hyperplasia, and associated PASH has been described in the adjacent tissue [328, 329].

Phyllodes Tumor Grading

Numerous studies have attempted to identify clinicopathologic factors that may be useful to stratify PTs for risk of local recurrence and metastasis. Histologic features have included tumor border, stromal cellularity, mitotic activity, stromal cell atypia, stromal overgrowth, tumor necrosis, and the presence of malignant heterologous elements [258, 261, 263, 293, 314]. The WHO grading system classifies tumors as benign, borderline, or malignant based on the degree of stromal hypercellularity, stromal cell atypia, and stromal mitotic activity, as well as presence or absence of stromal overgrowth, infiltrative tumor borders, and/or malignant heterologous elements (Table 7.1) [252]. Histologic grading of PTs overall correlates with risk of recurrence or metastasis, but can be problematic due to the inherent subjectivity of the grading criteria and diagnostic thresholds used, with lower predictive power for determining individual tumor behavior [252, 257, 330].

Table 7.1 Phyllodes tumor grading, WHO criteria

Full size table

Benign PTs are well-circumscribed, mildly hypercellular tumors with no to mild stromal cell atypia, low mitotic activity (0–4 mitotic figures/10 HPF) and pushing borders (Fig. 7.16). Stromal overgrowth and tumor necrosis are absent [252, 288]. Mature mesenchymal metaplasia may be seen very rarely and is often lipomatous when present [331]. Benign PTs are more likely to demonstrate PASH, multinucleated stromal giant cells, and epithelial hyperplasia than higher grade tumors [288].

On the other end of the spectrum, malignant PTs are characterized by areas of marked stromal cellularity, marked stromal cell atypia, and high mitotic activity (≥10 mitotic figures/10 HPF). The tumor border is at least focally infiltrative. Tumor infiltration may be obvious as tongues of infiltrating cellular stroma or may be more subtle, with wrapping and entrapment of adjacent fat. Stromal overgrowth is usually present and may be diffuse (Fig. 7.27). In fact, malignant PTs can mimic metaplastic spindle cell carcinoma or sarcoma due to the lack of or scant amount of epithelium, especially in CNBs (Figs. 7.28 and 7.29). Extensive sampling may be required (Fig. 7.30, 7.31, and 7.32). All five histologic features (marked cellularity, marked pleomorphism, ≥10 mitoses/10 HPF, permeative borders, and stromal overgrowth) should be present for a diagnosis of malignancy in the absence of malignant heterologous elements (Table 7.1) [252, 313]. Aside from liposarcoma-like differentiation, malignant heterologous stromal elements, such as chondrosarcoma, osteosarcoma, and rhabdomyosarcoma, define malignancy even in the absence of the other histologic features. A combination of heterologous components may be present (Fig. 7.23) [252, 257, 332,333,334,335]. Although liposarcomatous differentiation was previously considered to be diagnostic of malignancy in PT, these tumors are thought to have low metastatic risk, and liposarcoma-like differentiation in a PT alone is no longer considered a feature of malignancy [252, 336]. Consistent with this, despite the histologic similarity, PTs with liposarcoma-like elements lack MDM2 or CDK4 amplifications characteristic of extramammary well-differentiated liposarcomas [222, 337, 338]. Furthermore, the liposarcoma-like components of microdissected tumors were found to have less chromosomal aberrations than the non-heterologous component of the same tumors [222]. Accordingly, grading of PT with liposarcoma-like elements should be based on the other histologic parameters, akin to PTs without heterologous differentiation. For cases that do not meet criteria for malignancy using these features, it has been suggested to use the term “lipoblast-like areas” rather than liposarcoma to avoid confusion [339]. PTs with pleomorphic liposarcoma component may have worse outcomes [336].

Borderline PTs have intermediate histologic features between benign and malignant tumors (Table 7.1), and PTs with some but not all of the features of malignancy are classified as borderline (Fig. 7.17). Accordingly, these tumors have a varied morphologic appearance with a spectrum of stromal cellularity, atypia, and mitotic activity, but typically show mild or moderate stromal cellularity and/or mild to moderate stromal cell atypia with 5–9 mitotic figures/10 HPF. The tumor borders are often well-defined and pushing but may be focally infiltrative. Areas of stromal overgrowth can be seen but is not diffuse. Benign and borderline tumors may show significant heterogeneity [252].

In general, PTs should not be graded on CNB material. Choi et al. directly compared 129 PTs diagnosed and graded on excision specimens with the diagnosis and grade obtained in the preceding CNBs. Of 90 benign PTs, ~74% were correctly diagnosed and graded as benign PT in the CNB, with the remainder incorrectly diagnosed as FAs. Among 30 borderline and 9 malignant PTs, only ~27% and ~45% were correctly graded in the preceding CNB, respectively. All discordant diagnoses were underestimated on CNB in this study [292]. Another study found some correlation of stromal cellularity, pleomorphism, and mitotic activity between CNBs and excisions of PTs, with correlation coefficients of 0.6, 0.65, and 0.67, respectively. The degree of certainty increased with increasing tumor grade [340]. Discrepancies between grade on CNB versus excision are due to sampling, PT heterogeneity, and inability to evaluate the tumor borders, not to mention the difficulty discerning cellular FA from PT on CNB.

Recurrent and Metastatic Phyllodes Tumors

Local PT recurrences are most commonly of the same grade as the initial tumor [257, 258, 287]. In a large study, locally recurrent PTs were of the same grade as the initial tumor in 63% of 73 cases. Of 48 initially benign recurrent tumors, 21 (44%) recurred as higher grade, with most (81%) of these being borderline. Four (8.3%) of 48 benign tumors and 2 (12.5%) of 16 borderline tumors recurred as malignant tumors. Four (25%) borderline tumors but no malignant tumors recurred as benign lesions [257].

Metastatic PTs are essentially always comprised only of the stromal component, which demonstrates malignant spindle cell morphology in the vast majority of cases (Fig. 7.33). Heterologous sarcomatous elements present in the primary tumor may or may not be present in the metastasis [317, 332]. On the other hand, the metastatic tumor may very rarely demonstrate heterologous differentiation not seen in the primary tumor [341]. Only one unusual immunohistochemically confirmed case of PT with both epithelial and stromal metastasis to the lung has been reported [342].

Immunohistochemistry

Whereas the stromal cells of most FAs diffusely express CD34, such staining is less predictable in PTs and can be negative or variably positive (Fig. 7.28) [157, 159, 160, 343,344,345]. Stromal CD34 positivity decreases with increasing PT grade [160, 344,345,346,347,348]. One large study showed CD34 positivity in ~73% of 109 PTs, which decreased from ~79% of benign tumors to ~67% and ~44% of borderline and malignant tumors, respectively [345]. In a study of 57 CNBs designed to identify features that could predict PT on excision, all three CNBs that lacked CD34 staining were PTs on excision (two borderline and one malignant), whereas diffuse staining was seen in FAs and other PTs [349]. Stromal actin expression has been positively correlated with grade [344]. Sapino et al. observed stromal cell co-expression of ERβ, SMA, and calponin but no expression of ERα. In contrast to FAs, ERβ expression in PTs increased with age [163]. Stromal cells in PTs of all grades may express nuclear β-catenin (Fig. 7.28) [161, 162, 347, 350]. In a study of 119 PTs, Sawyer et al. observed stromal nuclear β-catenin staining in 86 (72%) tumors, with 7 of 8 malignant tumors showing absent or weak staining [350]. Others have also shown lower numbers of malignant PTs with staining [351]. CTNNB1 mutations have not been identified [161, 210, 211, 222, 350, 352].

Earlier studies reported absence of stromal cytokeratin staining in PTs, suggesting utility in the differential diagnosis with spindle cell metaplastic carcinoma [343, 353, 354]. More recent studies have shown cytokeratin staining in PTs. In a study by Chia et al., MNF116 was positive in ~12%, 34βE12 in 22%, CK7 in ~28%, CK14 in ~2%, AE1/3 in ~8%, and CAM5.2 in ~2% of PTs. Stromal MNF116, 34βE12, and CAM5.2 positivity increased with tumor grade, and MNF116 also increased with cellularity, necrosis, and cystic change [345]. Staining in all positive cases was focal in this study, ranging from 1 to 5% of tumor cells [345]. Cimino-Mathews et al. described focal cytokeratin (AE1/3, 34βE12, or CK8/18) positivity in 1–5% of stromal cells in 3 (21%) of 14 malignant PTs but no FAs, benign or borderline PTs [346]. Earlier studies also reported lack of p63 staining in PTs [355,356,357]. More recent analysis revealed p63 positivity in stromal cells of 8 (57%) of 14 malignant PTs, but no staining in FAs, benign or borderline PTs [346]. Staining in most (63%) p63-positive malignant PTs was focal (1–5% of tumor cells), with none showing staining in >30% of cells. The ΔN p63 isoform p40 was expressed in 14% of malignant PTs but no benign or borderline PTs or FAs. Bansal et al. also described focal p63 and cytokeratin cocktail staining in 2 of 10 malignant PT but not in benign or borderline PT [358]. Differences in cytokeratin and p63 expression in PTs between earlier and more recent studies may be attributed to preferential staining of these markers in malignant PTs, few of which were included in earlier studies [346]. The findings have special relevance to CNB diagnosis, as positive staining for cytokeratins, p63, or p40 in spindle cell lesions cannot be used to exclude PT (Figs. 7.31, 7.32, and 7.34).

Many studies have evaluated the correlation of immunohistochemical markers with PT grade, histologic features used for grading, and/or recurrence or metastasis. These have included p53 [359,360,361,362,363,364,365,366,367,368,369,370], TERT [371], CD117 [344, 348, 368, 372,373,374,375], CD10 [165, 376], EGFR [377, 378], PDGF and PDGFRβ [379], VEGF [347, 380], and Ki-67 [359, 367, 381,382,383,384,385]. None were shown to independently predict recurrence or metastasis. In a study by Cimino-Mathews et al., 29% of malignant PTs showed diffuse strong p16 expression with RB loss, and 21% of malignant tumors showed the reverse immunophenotype of p16 loss with diffuse strong RB expression (Fig. 7.33). No FAs, benign or borderline PTs had this immunophenotype, suggesting that this pathway may contribute to PT progression in a subset of tumors [381].

The epithelial cells of PTs usually express ER and PR, and an inverse correlation with malignancy has been reported [386].

In a study designed to identify features of cellular fibroepithelial tumors that predict PT on subsequent excision, Jacobs et al. found significantly higher median stromal Ki-67 staining in biopsies of PTs (7.2%, range 0–18%) than cellular FAs (1.6%, range 0.4–4.4%), even among lesions of moderate stromal cellularity [127]. However, there was significant overlap, with CNBs from 3 of 9 PTs showing proliferative indices <4.4% [127]. Jara-Lazaro et al. reported that CNBs with stromal Ki-67 indices ≥5% were PTs on excision in 84% of cases, whereas all FAs showed no or <5% staining [349]. In practice, the significant degree of overlap in Ki-67 staining among fibroepithelial tumors precludes reliable diagnostic utility in most cases [127, 383].

Differential Diagnosis

The differential diagnosis of a cellular fibroepithelial tumor with mild to moderate stromal cellularity, no to minimal stromal cell atypia, and absent or low mitotic activity usually rests between benign PT and cellular FA (Table 7.2). The distinction of benign PT from cellular FA is often not problematic in an excision specimen if the lesion has well-developed frond-like architecture of PT and subepithelial stromal accentuation. However, not all PTs have well-developed stromal fronds, with the epithelium of some tumors arranged as elongated branching, clefted ducts, sometimes with a staghorn-like appearance (Fig. 7.19) [252, 313]. Lack of stromal fronds should therefore not necessarily exclude the diagnosis in the presence of other concerning features, such as increased stromal cellularity, mitotic activity, stromal atypia, stromal overgrowth, and/or infiltrative growth. On the other hand, focal stromal fronds may be seen in some FAs. These are generally focal and less cellular without subepithelial stromal accentuation (Fig. 7.15). Retracted stromal projections of some intracanalicular FAs can mimic stromal fronds, but these have the appearance of fitting together with one another like a jigsaw puzzle, as opposed to PT fronds that protrude more irregularly into gaping cystic spaces [127]. Assessment of stromal cellularity is subjective, and the lower threshold of PT cellularity overlaps with cellular FA. Significant and diffuse nuclear overlap or areas of sheet-like stromal growth are not features of cellular FA. Stromal cellularity and epithelial distribution is often heterogeneous in PTs, compared to the more uniform appearance of cellular FAs and juvenile FAs. This feature is more helpful when evaluating excision specimens than CNBs [126]. Although FAs are typically well-circumscribed, lesions otherwise indistinguishable from typical FAs may occasionally show irregular borders, which has also been documented in pediatric FAs [147]. In some cases, distinguishing cellular FAs from benign PTs may simply not be possible. In such cases, a diagnosis of benign cellular fibroepithelial neoplasm can be rendered, with an explanation of the features present, the difficulty in precise categorization, and the possible risk of local recurrence with essentially no risk for metastasis [126]. The diagnostic dilemma was highlighted in a study by Lawton et al., in which 21 fibroepithelial tumors that were difficult to classify as cellular FAs or PTs were independently reviewed by ten breast pathologists. Complete agreement among pathologists was seen in only two (9.5%) cases, and diagnoses ranged from FA to borderline PT in 43% of cases [387]. TERT promoter mutations are highly enriched in PTs compared to FAs (including cellular FAs) and may be useful to favor PT in challenging cases [205, 207, 210].

Table 7.2 Benign phyllodes tumor versus cellular fibroadenoma

Full size table

The distinction between cellular FA and PT is particularly problematic in CNBs (Figs. 7.35, 7.36, and 7.37). Patient age and tumor size are not useful in this context [127, 128, 340, 388]. Numerous studies have examined histopathologic features in CNBs of PTs compared to FAs [127, 128, 169, 340, 349, 388,389,390,391]. Many have identified stromal cellularity and/or mitotic activity to be useful in CNBs, with other features overall being less helpful (Fig. 7.35) [127, 128, 169, 340, 349, 391]. Jacobs et al. evaluated histopathologic features present in CNB diagnosed as fibroepithelial lesions with cellular stroma that could predict a diagnosis of PT versus FA on subsequent excision [127]. Only stromal cellularity (marked versus mild) and mitotic activity were found to be useful, with all markedly cellular lesions being PTs and all mildly cellular lesions being FAs. Mild cellularity was defined as twice the cellularity of normal perilobular stroma, and marked cellularity was defined as stromal cells in close contiguity “resulting in areas of confluence with many stromal cell nuclei appearing to touch.” Although PTs of moderate cellularity showed higher mitotic counts (1–6 mitoses/10 HPF) than cellular FAs (1–2 mitoses/10 HPF), broad overlap was seen. Similarly, median Ki-67 indices were higher for these PT (7.2%, range 0–18%) than cellular FAs (1.6%, range 0–4.4%), but overlap prevented practical use as a single diagnostic feature. The authors suggested a diagnostic algorithm in which markedly cellular lesions or moderately cellular lesions with stromal mitotic activity or elevated proliferative indices are most likely to be PTs, whereas mildly cellular lesions, especially if lacking mitoses or elevated proliferative fractions, are more likely to be FAs [127]. Lee et al. found that increased stromal cellularity compared to typical FA in at least 50% of the biopsy material, stromal expansion with a 10× microscope objective, tissue fragmentation and adipose tissue within lesional stroma were all significantly more common in CNBs from PTs compared to FAs (Figs. 7.35, 7.36, and 7.37) [169]. Tissue fragmentation likely reflects leaf-like growth, which is not always appreciated in CNBs. However, FAs with prominent intracanalicular growth may also fragment and form pseudofrond-like foci in CNBs, and this feature should be interpreted with caution (Fig. 7.37). A subsequent study applied these four features to CNBs of fibroepithelial tumors diagnosed as either PT or cellular FA on excision. This allowed for correct categorization in 19 of 21 PT and 70 of 91 FAs but predicted “unnecessary” excision of 31% of FAs [392]. Jara-Lazaro et al. studied fibroepithelial tumors in which PT could not be excluded on CNB and found that either marked stromal cellularity, marked nuclear atypia, stromal overgrowth (4× objective), ≥2 mitotic figures/10 HPF, or ill-defined lesional borders exclusively predicted PT on excision. Moderate stromal cellularity (20 of 27 PTs), moderate nuclear atypia (14 of 16 PTs) and PASH (19 of 23 PTs) were significantly more common in PTs. Of lesions with mild stromal cellularity, 42% were PTs on excision, whereas most lesions with moderate (74%) and all lesions with marked cellularity were PTs. Stromal mitoses of 0–1/10 HPF were present in similar numbers of PTs (42%) and FAs (58%), but all cases with 2 or more mitotic figures in 10 HPF were PTs. Eighty-four percent of lesions with Ki-67 index ≥5% and all lesions with topoisomerase labeling ≥5% were PTs on excision [349]. Yasir et al. used a combinatorial approach and concluded that the presence of any three or more of a number of different histologic features is useful in prediction of PT on CNB. These included mitotic activity, stromal expansion (10× objective), stromal fragmentation, adipose tissue infiltration or fat entrapment, stromal heterogeneity, stromal condensation, and stromal cell pleomorphism. More features were seen on average in PTs (3.9) versus FAs (1.4). No lesions with 0–1 features were PTs, whereas 70%, 87.5%, and 100% of lesions with 3, 4, or 5 features were PTs, respectively. In particular, the combination of stromal heterogeneity, subepithelial condensation, and stromal pleomorphism were considered most useful. The sensitivity for detection of PT was 85.2% for the detection of 3 or more histologic features and 74.1% for the detection of three or more mitotic figures [128]. Differences between these studies are likely due to the sample populations, inherent heterogeneity of PTs, and the subjectivity and thresholds of evaluated histologic parameters between observers, which limits practical application. No feature(s) have been found to reliably predict PT versus FA in all cases. A CNB diagnosis of fibroepithelial neoplasm with cellular stroma is prudent in equivocal cases, with recommendation for excision.

On occasion, a spindle cell proliferation with associated benign epithelium can raise the differential of fascicular PASH versus cellular fibroepithelial tumor on CNB of a breast mass. The presence of fat within the lesion can especially raise concern for an infiltrative fibroepithelial tumor. The possibility of PASH within a fibroepithelial tumor may also be considered. Careful evaluation for fibroepithelial architecture (elongated and compressed ducts, subepithelial stromal growth) or other areas with classic PASH can point to the correct diagnosis.

The differential diagnosis of malignant PT primarily includes metaplastic carcinoma, primary and metastatic sarcoma, and melanoma (Table 7.3). If biphasic intracanalicular growth is recognized, the diagnosis of PT is straightforward (Fig. 7.27a, b). Atypical or frankly malignant epithelium (invasive or in situ) favors metaplastic carcinoma and is much less common in PTs and absent in sarcomas. Tumors consisting only of malignant spindle cells without an epithelial component are most problematic. In the breast, metaplastic carcinoma is more common than malignant PT (and sarcoma) and should be excluded in such cases. Extensive sampling of an excision specimen may be required to identify the epithelial component of PT, which may be very focal (Figs. 7.30, 7.31, and 7.32). Malignant heterologous elements can be seen in PTs, metaplastic carcinomas, and sarcomas and is not a useful differentiating factor (Fig. 7.29), with the exception of liposarcoma-like areas that would favor PT and essentially exclude metaplastic carcinoma.

Table 7.3 Differential diagnosis of malignant spindle cell neoplasms of the breast

Full size table

The distinction between malignant PT with stromal overgrowth, metaplastic carcinoma, and sarcoma can be especially difficult in CNBs showing a malignant spindle cell neoplasm (Figs. 7.28, 7.29, 7.30, 7.31, 7.32, 7.34 and 7.38). The distinction has clinical implications, as patients with metaplastic carcinoma may undergo axillary sentinel node sampling at time of surgery, and neoadjuvant chemotherapy may be considered. Immunohistochemistry can sometimes be useful if pitfalls are avoided. Metaplastic carcinomas express cytokeratins, especially high-molecular-weight keratins 34βE12, CK5/6, CK14, and AE1/3, although the type and extent of cytokeratin staining varies between tumors and can be focal [346, 353, 357, 393,394,395]. However, PTs may also show focal (1–5%) cytokeratin positivity, including MNF116, 34βE12, CK7, CK8/18 CK14, AE1/3, and CAM5.2 (Figs. 7.31 and 7.34). MNF116, 34βE12, and CAM5.2 positivity increases with PT grade, and was only seen in malignant PT in one study [345, 346]. Metaplastic spindle cell carcinomas often express p63 [346, 356, 357, 396], but this marker can also be expressed in malignant PTs (57% in one study), as well as reactive stromal proliferations (Figs. 7.31, 7.32, and 7.34) [346, 397]. In one tissue microarray (TMA) study, 57% of malignant PTs were p63 positive (weak or moderate to strong intensity), with focal staining (1–5% of cells) in most (63%) of these cases and <30% of cells staining in all cases. In contrast, 62% of spindle cell carcinomas were p63 positive, which was of moderate to strong intensity in 20–100% of cells [346]. Accordingly, strong diffuse p63 and/or cytokeratin staining favor metaplastic carcinoma, but negative or focal staining is not informative. It has been suggested that p40 expression may be more specific (86% vs. 43%) but less sensitive (46% vs. 62%) than p63 for metaplastic carcinoma versus malignant PT [346]. CD34 is negative in metaplastic carcinomas and may be positive in PTs, but expression decreases with PT grade, such that many malignant PTs (43% in one study) are negative [160, 398]. Positive CD34 staining essentially excludes metaplastic carcinoma, whereas negative staining is not informative (Figs. 7.28, 7.30 and 7.32). In a TMA study, 7 of 13 metaplastic carcinomas (2 of 6 with spindled morphology) expressed GATA3, including 4 cases with at least 25% of cells staining positively, compared to only 1 of 14 malignant PTs, which showed weak staining in 6–25% of cells [29]. Another study observed GATA3 expression in most metaplastic carcinomas but in none of 33 (including 8 malignant) PTs [399]. The neural crest transcription factor SOX10 was found to be expressed in 66% of metaplastic carcinomas versus no PTs, including 14 malignant tumors [400].

In challenging cases, targeted genetic analysis can be useful in distinguishing malignant PT from metaplastic carcinoma (Figs. 7.29, 7.32 and 7.34). MED12 mutations are the most frequent mutations in PTs with discriminatory potential in this context, having been identified in up to ~40% of malignant PTs across studies but not in metaplastic carcinomas [205, 210, 211, 222, 352, 401,402,403,404,405,406,407,408,409].

Sarcomas may be morphologically indistinguishable from malignant PTs with complete stromal overgrowth. Exclusion of metastatic sarcoma is facilitated by clinical history. Primary breast sarcomas have identical features as in extramammary sites but, aside from angiosarcomas, are exceedingly rare in the breast and a diagnosis of exclusion. In one study, 5 of 6 tumors diagnosed as primary breast sarcomas were found to have genetic features of PTs (MED12, TERT, FLNA, and/or BCOR mutations), suggesting that these tumors have similar origins [410]. Clinicopathologic features and outcomes have been shown to be similar between PTs and primary breast sarcomas [411].

In the absence of a recognized biphasic component on CNB, the differential diagnosis also includes other spindle cell tumors. Although most fibromatoses express nuclear β-catenin, this marker is not specific in this context, being positive in some PTs and metaplastic carcinomas [350, 412]. Fibromatosis is CD34 negative. Melanomas and nerve sheath tumors are often SOX10 and S100 protein positive, and melanomas may express other melanocytic markers. Myofibroblastomas do not typically entrap epithelial elements, facilitating distinction from PTs with evidence of biphasic growth. Myofibroblastomas and PTs can be CD34 and SMA positive, but myofibroblastomas often express ER, PR, and AR, and may be more diffusely desmin positive, in contrast to PTs. Genetic analysis can also be helpful to distinguish PTs from other spindle cell lesions. Identification of a MED12 exon 2 mutation favors a fibroepithelial tumor [413], and other aberrations can point to the alternate diagnosis (i.e., CTNNB1 or APC mutations in fibromatosis, gene fusions specific to sarcoma types).

Pathogenesis, Molecular Pathology, and Risk Factors

PTs derive from specialized intralobular stroma. Early clonality studies showed that the stroma is monoclonal [197,198,199, 201, 414], with a monoclonal epithelial component identified in some tumors [197, 415]. Epithelial-stromal interactions have been suggested to play a role in PT pathogenesis. Consistent with this, stromal cellularity and mitotic activity is increased in subepithelial zones [416]. Wnt/β-catenin signaling has been implicated. Sawyer et al. found stromal β-catenin nuclear staining without CTNNB1 mutations in PTs, with a direct correlation between epithelial Wnt ligand Wnt5a and stromal nuclear β-catenin expression in benign but not malignant PTs. Thus, epithelial-derived Wnt signaling may contribute to tumor development via stromal β-catenin activation, with stromal proliferation becoming independent of the epithelium during tumor progression [350, 416]. Additional evidence supportive of epithelial-stromal interaction in PT pathogenesis can be inferred from correlations between epithelial marker expression (ER, PR, E-cadherin) and stromal histologic features or grade [386, 417].

MED12 exon 2 mutations identical to those identified in FAs have been identified in stromal cells of PTs, and other genes (RARA, SETD2, KMT2D, FLNA, among others) are also recurrently mutated in both tumors [205, 208,209,210,211, 222, 401, 418], supporting a shared pathogenesis. Using a targeted sequencing panel of 16 genes implicated in fibroepithelial tumor pathogenesis, PTs were more likely to harbor multiple mutations compared to FAs, including when comparing only benign PTs to FAs [205]. Some PTs likely arise from FAs, although this remains controversial. Observational support for this hypothesis derives from the similar morphology and genetic profiles of both tumors, the relatively high frequency of FAs in patients with PTs, and the identification of FA-like areas in some PTs [258, 324]. More direct genetic evidence was first provided by Noguchi et al., who found evidence of stromal monoclonality with alteration of the same AR allele in three FAs that subsequently recurred as PTs [199]. More recently, studies of synchronous and metachronous ipsilateral fibroepithelial tumors revealed identical MED12 mutations in paired FAs and PTs (including benign and malignant tumors), indicative of clonal relatedness [211, 419]. Furthermore, PTs with FA-like areas were found to be genetically distinct from PTs without FA-like areas [420]. In this context, the increased frequency of mutations in RARA, TERT, FLNA, and SETD2 in PTs compared to FAs may additionally implicate these genes in progression to PT [205, 211, 212, 419]. Nonetheless, the high prevalence of FAs and relative rarity of PTs suggests that an event causing progression of FA to PT would be exceptionally rare [339].

Genetic features associated with grade progression among PTs have been characterized. TERT alterations, including promoter mutations, correlate with tumor grade and are among postulated drivers of tumor progression [205, 210, 222]. TERT alterations have been associated with increased TERT mRNA and TERT protein expression in stromal cells of PT [210, 371]. In the largest studies, TERT alterations were identified in 18–32% benign, 57–61% borderline, and 46–68% malignant tumors [205, 210, 212, 371]. TERT promoter mutations have only rarely been identified in FAs [205, 212]. Increased telomerase activity stemming from TERT aberrations may help overcome replicative senescence and allow for accumulation of additional aberrations during tumor progression [210, 339]. Mutations in FLNA, TP53, and RB1 have also been found to correlate with increasing grade, and PTEN aberrations were enriched (11%) in malignant tumors [205], whereas MED12 mutations appear to correlate negatively with grade, being less frequent in malignant PTs [205, 210]. Some studies identified TP53, RB1, NF1, PIK3CA, and EGFR aberrations exclusively in borderline or malignant tumors [210, 211, 401]. A pathogenic role for the tumor suppressor TP53 is further supported by the finding that women with Li-Fraumeni syndrome harboring germline TP53 mutations are susceptible to PT development [421]. Liu et al. identified genetic aberrations in tyrosine kinase (FGFR1/EGFR) and PI-3 kinase signaling pathways in 8 of 10 malignant phyllodes tumors , including activating FGFR1, PIK3CA, and BRAF mutations [222]. Activating hotspot mutations in AKT1, NRAS, ERBB2, and ERBB3, as well as KIAA1549-BRAF and FGFR3-TACC3 gene fusions, have also been found in low frequency in malignant PTs [210, 352, 422]. Several of these aberrations are potentially targetable and could suggest therapeutic options for these aggressive tumors. Higher grade PTs also have increased karyotypic complexity with increased chromosomal copy number changes relative to lower grade tumors [201, 415, 423,424,425,426,427]. Recurrent 1q gain and 13q loss have been associated with borderline/malignant grade [426,427,428,429,430,431]. Gains of 7p and 8q, losses of 10 and 13q, losses in 9p21.3 (CDKN2A/B), and amplifications, including EGFR, are potential markers of malignant tumors [425].

There is evidence for MED12-dependent and MED12-independent pathways in PT development. In a study of 16 borderline and malignant PTs, Pareja et al. compared the genetic profiles of 7 PTs with FA-like areas and 9 PTs without FA-like areas and found MED12 mutations to be significantly more frequent in the group with FA-like areas (71%) compared to the group without FA-like areas (11%), which had more frequent aberrations in EGFR, TP53, and RB1. The authors speculate that some borderline and malignant PTs may develop from MED12-mutated FAs, whereas others arise de novo via accumulation of genetic aberrations in other cancer drivers [420]. Consistent with the concept of multiple pathogenic pathways, others have found more frequent aberrations in TERT, RARA, SETD2, EGFR, ERBB4, MAP3K1, and IGF1R in MED12-mutated tumors compared to MED12-wild-type tumors, which instead more often harbored TP53 and PIK3CA mutations [205]. In this context, it is interesting that patients with malignant PT and a history of ipsilateral FA had a significantly longer survival than those without FA history [432], and MED12-mutated PTs had a lower recurrence rate than MED12-wild-type tumors [433].

Genetic analysis has uncovered intratumoral genetic heterogeneity in PTs, which at least in some cases, correlates with morphologic heterogeneity. Regions of increased stromal cellularity and atypia have been found to have increased mutational burden [434] and more chromosomal copy number changes and pathogenic mutations [222], compared to regions of less cellularity and atypia within the same tumors. Liu et al. additionally described more chromosomal aberrations in non-heterologous areas compared with liposarcomatous foci in microdissected PTs [222]. Histologically similar regions within PTs have also been shown to display differences in chromosomal copy number alterations, and acquired chromosomal aberrations in recurrent versus primary tumors were independent of histologic progression. These findings may provide an explanation for the imperfect correlation between histologic grading and tumor behavior and progression [330, 424].

Prognosis and Clinical Management

Local Recurrence

Most PTs are benign, and only a minority of tumors recur locally following excision [252]. In a large series of 605 PTs, the overall recurrence rate was ~13%, with the majority (91%) being local [257]. Most local recurrences occur within 2–3 years of diagnosis, although intervals greater than 20 years have been reported [252, 257, 258, 260, 263, 285, 287, 288, 293, 314]. In one study, 65% of patients experienced a single tumor recurrence, with 2, 3, and 6 recurrences occurring in ~29%, 5%, and ~1%, respectively [257]. Most local PT recurrences are of the same grade as the original tumor, although some may be higher grade [257, 287, 435]. In one study, the overall rate of progression of initially benign or borderline tumors to a higher grade recurrence was 31.5%. Twenty-one of 48 (~44%) initially benign tumors and 2 of 16 (~13%) initially borderline tumors recurred as higher grade, with ~9% (6 of 64) benign or borderline tumors recurring as malignant [257].

Recurrence risk has been correlated with tumor grade. A recent meta-analysis of 54 studies with a total of 9234 patients identified a local recurrence risk of 6–9%, 11–16%, and 14–21% for benign, borderline, and malignant PTs, respectively [436]. Features that have been correlated with increased recurrence risk include stromal mitotic activity, stromal cellularity, stromal pleomorphism, stromal overgrowth, myxoid stroma, tumor necrosis, infiltrative borders, and younger age [257, 258, 285, 288, 436,437,438]. Tan et al. developed a nomogram based on stromal cell atypia, mitotic activity, stromal overgrowth, and surgical margins (AMOS criteria) that could predict recurrence-free survival more accurately than an aggregate sum of predictive histologic factors. Although the nomogram does not distinguish between local recurrence and metastasis, the vast majority of events in this study were local [257]. The nomogram has been validated in other patient populations [20, 324, 439]. Positive surgical margin status has also been implicated as a strong predictive factor for local recurrence in numerous other studies [34, 255, 258, 260, 261, 286, 292, 438,439,440,441]. However, a recent meta-analysis identified a correlation between positive margin status and local recurrence for malignant PTs only, with a tendency for increased recurrence in benign and borderline tumors [436]. Furthermore, several recent studies have suggested that benign PTs have low recurrence risk that may be independent of margin status [287, 435, 436, 442,443,444,445,446,447].

Metastases and Survival

Axillary metastases of PTs are rare, and distant metastases are also uncommon, estimated to occur in ~2% of cases overall [252, 435, 448]. Essentially only malignant PTs metastasize, often after local recurrence [252, 257, 258, 288, 293, 300, 438]. Metastases usually occur within 5 years of diagnosis [252, 258, 263, 285, 287, 293, 449]. The most common sites of metastatic spread are lung and pleura, with less common sites including vertebrae, bones, gastrointestinal tract, and liver, among others [34, 257, 263, 314, 438, 449]. Metastases are essentially always comprised only of the stromal component. Predictors of metastasis include older age (>50 years) and indicators of tumor biology, such as stromal overgrowth, diffuse and marked stromal atypia, necrosis, infiltrative border, high mitotic count, size (>9 cm), and heterologous differentiation [258, 260, 314, 449,450,451,452]. In a large series of 605 PTs, 2% of women died of PT [257]. Deaths typically occur with malignant PT preceded by metastasis [288, 293, 314]. Local recurrence with chest wall invasion may also rarely be fatal [293]. Reinfuss et al. reported a median survival of 4 months for patients with metastatic disease, and in another study it was 17 months [438, 453].

Treatment

The primary treatment for PTs is surgical excision. Breast conserving surgery is typically preferred if feasible. Mastectomy has been performed if breast conserving surgery is not possible due to large tumor size and/or high tumor to breast ratio or for recurring disease [34, 262, 285, 438, 441, 448, 454,455,456,457]. The likelihood of PT when CNB reveals a fibroepithelial tumor with cellular stroma is relatively high. In one study directly evaluating outcomes of patients with cellular fibroepithelial lesions initially diagnosed in CNBs, 41% of patients were found to have PT on excision [127]. In another study in which PT could not be excluded on CNB, 63% of patients had PT on excision [349]. In this context and due to the uncertainty and challenges in differentiating cellular FA from PT, surgical excision is often warranted for cellular fibroepithelial lesions identified on CNB [126]. Whereas FAs are routinely enucleated, PTs have typically been excised with the goal of achieving negative margins [34, 438, 448]. However, recent studies suggest that benign PTs have low recurrence risk that may be independent of margin status and may not require wide excision [255, 287, 435, 436, 442,443,444,445,446,447]. Guidelines from the National Comprehensive Cancer Network (NCCN), 2021 recommend excisional biopsy with complete mass removal but without the goal of obtaining negative margins, followed by observation, for indeterminate fibroepithelial tumors or benign PTs identified on CNB. Fibroepithelial tumors with features concerning for borderline or malignant PT on CNB should be excised to negative margins [458]. Fibroepithelial tumors involved by atypical hyperplasia or carcinoma are excised and managed according to guidelines for these lesions [458].

Adequate margin width for PT excision is controversial, and the adequate distance to negative margins has not been prospectively evaluated. A rim of at least 1 cm of uninvolved tissue has often been cited based on retrospective analyses [34, 258, 297, 438, 458]. However, this margin width is not consistently obtained in practice, and it is unlikely to be necessary for all PTs [435]. Recent studies and meta-analyses have failed to identify significant correlations between negative margin width and local recurrence [435, 437, 459,460,461,462,463]. This is particularly relevant in benign PTs, for which emerging data suggest that wider excision is unlikely to have significant impact on local recurrence [255, 287, 435, 436, 442,443,444,445,446,447]. The minimum width of a negative margin in borderline and malignant PTs remains uncertain, but several studies have suggested that 1 cm margins may not be necessary [437, 459, 462, 464, 465]. An expert consensus review has suggested that tumor on ink or <1 mm away be considered positive for PTs [313]. On the other hand, the NCCN currently recommends a 1 cm margin for borderline and malignant PTs, while noting that narrower margins are not an absolute indication for mastectomy [458].

Given the very low incidence of axillary nodal metastasis in PTs, axillary sentinel lymph node biopsy or dissection is not routinely indicated in the absence of concurrent invasive carcinoma or confirmed nodal metastasis [34, 435, 448, 458].

There are no randomized controlled prospective data to support the use of adjuvant radiation therapy for PT, and its routine use has not been established. However, patients with borderline and especially malignant tumors may be offered radiation treatment [262, 285, 297, 339, 455, 456, 466]. In a study using Surveillance, Epidemiology, and End Results Program (SEER) data from 1983 to 2013, 11% and 16% of patients with malignant PTs undergoing breast conserving surgery or mastectomy, respectively, were treated with adjuvant radiation [467]. Some studies have reported a decrease in local recurrences with use of adjuvant radiotherapy, but without an effect on survival [297, 467,468,469,470,471,472]. The NCCN guidelines suggest that radiation could be considered if recurrence could create significant morbidity, such as chest wall recurrence following mastectomy [458]. There is no proven benefit for chemotherapy in the treatment of PTs, which may be considered on a case-by-case basis in malignant tumors [339, 448, 473].

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Department of Pathology, University of California San Francisco, San Francisco, CA, USA
Gregor Krings & Yunn-Yi Chen

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Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY, USA
Sandra J. Shin
Department of Pathology, University of California San Francisco, San Francisco, CA, USA
Yunn-Yi Chen
Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
Paula S. Ginter

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Krings, G., Chen, YY. (2022). Fibroepithelial Lesions. In: Shin, S.J., Chen, YY., Ginter, P.S. (eds) A Comprehensive Guide to Core Needle Biopsies of the Breast . Springer, Cham. https://doi.org/10.1007/978-3-031-05532-4_7

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DOI: https://doi.org/10.1007/978-3-031-05532-4_7
Published: 24 November 2022
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Fibroepithelial Lesions

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Fibroepithelial Lesions

Fibroepithelial Lesions of the Breast

Fibroepithelial Lesions

Keywords

Mammary Hamartoma

Overview and Clinical Presentation

Gross and Radiologic Features

Microscopic Features

Immunohistochemistry

Differential Diagnosis

Pathogenesis and Risk Factors

Prognosis and Clinical Management

Fibroadenoma

Overview and Clinical Presentation

Gross and Radiologic Features

Microscopic Features

Immunohistochemistry

Differential Diagnosis

Pathogenesis and Risk Factors

Molecular Pathology

Prognosis and Clinical Management

Risk of Development of Subsequent Carcinoma

Clinical Management and Outcomes

Phyllodes Tumor

Overview and Clinical Presentation

Gross and Radiologic Features

Microscopic Features

Histological Features

Phyllodes Tumor Grading

Recurrent and Metastatic Phyllodes Tumors

Immunohistochemistry

Differential Diagnosis

Pathogenesis, Molecular Pathology, and Risk Factors

Prognosis and Clinical Management

Local Recurrence

Metastases and Survival

Treatment

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