Fibroepithelial Lesions of the Breast: Update on Molecular Profile With Focus on Pediatric Population Open Access

FAs are the most common benign tumors of the breast. Natural history of FA varies, but the common presentation is younger age (younger than 35 years), with the exception of complex FAs, which usually occur in the older age group. Most FAs grow for a 12-month period, increasing to a size of 2 to 3 cm, and remain unchanged in size afterward for several years. Regression or complete resolution occurred in 16% to 59% of all cases followed up to 29 years.⁹  It is postulated that the probability of resolution is 50% and the lifetime expectancy is about 15 years in FA.⁹  Clinically, FAs present without symptoms and as smaller lesions than PTs (usually <3 cm). FAs are hormone sensitive and therefore their size can vary depending on menstrual cycle changes, with an increase in size during pregnancy and regression after menopause. Occasionally, giant FAs (>5 cm) can occur in adolescent girls and adult patients.¹⁰  Juvenile FAs are most commonly seen in adolescent patients. They can be quite large (3–10 cm) and grow rapidly.¹¹  Use of cyclosporine in transplant patients has been linked to multiple large and/or bilateral FAs.¹²  Most FAs occur sporadically, and there is a small association with Carney complex, particularly in myxoid FA.¹³  Occasionally, FAs can occur in men with gynecomastia.¹⁴ 

PTs are uncommon as compared to FAs. They usually occur in a patient population older than that with FA, with an age range of 40 to 50 years, and have an average tumor size of 4 to 5 cm. Most have a benign clinical course. Historically, PTs were named cystosarcoma phyllodes because of their cystic and leaflike growth pattern. They usually present as a large, firm, and painless mass. In 1960, the term tumor phyllodes was proposed to avoid the implication of different biologic behavior in this group of lesions.^15,16  On the basis of biological behavior and morphology, PTs are subclassified into 3 grades: benign, borderline, and malignant. In general, malignant PTs grow faster than benign PTs, and sudden growth of a preexisting mass also suggests PT. Rarely, multifocal or bilateral masses can occur. As the size of a PT gets larger (>10 cm), the overlying skin can ulcerate; thus, skin ulceration should not be used as an indication of malignancy. Also, in large PTs, paraneoplastic syndromes (hypoglycemia secondary to insulin-like growth factor secretion, hypertrophic osteoarthropathy) have been described.^17,18  Reactive axillary nodes are relatively common in PT owing to tumor infarction or necrosis,¹⁹  but axillary nodal metastasis is rare for PT.²⁰ 

FELs are very common and account for up to 90% of all solid breast tumors in the pediatric patient population.²¹  Although both FA and PT can occur in this age group, most cases are FAs.²²  Since FAs (both conventional and juvenile types) tend to have features such as increased stromal cellularity and leaflike structures and they tend to grow faster and larger than those in adult patients, they can be easily confused with PT; regardless, it is critical for pathologists to render a correct diagnosis for these lesions.

Grossly, FAs are solid, well-circumscribed masses, usually less than 3 cm and with white, tan, rubbery cut surfaces. Morphologically, FA and its variants are characterized by the proliferation of both epithelial and stromal components in intracanalicular or pericanalicular patterns that involve the terminal ductal lobular unit (Figure 1, A and B). Both patterns may present in the same lesions and are not associated with any clinical significance; however, recent molecular studies have shown that MED12 mutations are more frequently seen in FA with intracanalicular pattern.²³  The Pericanalicular pattern is more commonly seen with juvenile FA. The stromal component is usually low in cellularity, has no atypia, and has no or rare mitoses (except in young or pregnant women). Multinucleated giant cells with nuclear atypia can be seen²⁴ ; however, there is no prognostic significance to these cells.^25,26  Occasionally, calcifications, ossifications, pseudoangiomatous stromal hyperplasia, or lipomatous metaplasia can occur in FA. FAs carry minimal risk (2.17 times that of the control group) for breast cancer²⁷ ; moreover, FAs with atypical hyperplasia have no increased cancer risk when compared to FAs without atypical hyperplasia if the atypia is limited within the FA.²⁸ 

Most of the misclassification for FA comes from variants of FA, as they may show many overlapping features with PT, especially cellular FA and juvenile FA. Cellular FAs have mild to moderately increased cellularity in the stroma with pericanalicular growth (Figure 2, A and B). Sometimes, cellular FA can be difficult to differentiate from an area of borderline PT on morphology alone, especially in core biopsies.²⁹  Juvenile FA can occur in both the pediatric and adult populations, so age should not be used as a criterion for differential diagnosis. Juvenile FAs are characterized by increased stromal cellularity and the presence of gynecomastia-like usual ductal hyperplasia³⁰  (Figure 2, C and D). Epithelial atypia in juvenile FA should be interpreted conservatively.³¹  Complex FA is considered as a diagnosis if one of the following features are present: sclerosing adenosis, cysts at least 3 mm in size, papillary apocrine metaplasia, and epithelial calcifications (Figure 2, E and F). Complex FAs are smaller than the conventional type and tend to occur in the older age group. They have been shown to be associated with increased cancer risk, but whether it is truly due to the lesion itself or due to its association with older patients is not clear.³²  Myxoid FAs are characterized by FAs with loose myxoid hypocellular stroma (Figure 2, G and H). They are associated with Carney complex, which is characterized by the presence of myxomas, spotty pigmentation, and endocrine overactivity.¹³  So far, MED12 mutation has not been detected in myxoid FA.³³ 

Grossly, PTs are circumscribed, bulging masses, with tan-flesh cut surfaces. They originate from intralobular and periductal stroma; the significant changes for PTs are the presence of increased stromal cellularity and leaflike structures that are lined by luminal epithelial and myoepithelial cell layers. Increased stromal cellularity, especially adjacent to the epithelium, is referred to as periepithelial or subepithelial condensation. An exaggerated intracanalicular growth pattern develops into prominent leaflike structures (Figure 3, A and B). Some variants of FA, such as cellular FA, can have increased stromal cellularity, and juvenile FA and conventional FA in pediatric patients can have both increased stromal cellularity and limited leaflike structures. In those incidences, they can be confused with PT. Heterogeneity—that is, the uneven distribution of hypercellular stroma areas and the glandular elements within the tumor—and the presence of different types of stroma (eg, hypercellular, hypocellular, hyalinized, and myxoid areas) suggest a diagnosis of PT, not FA.³⁴ 

The 2019 World Health Organization (WHO) edition for breast tumor classification¹  recommends that PT be graded as benign, borderline, or malignant on the basis of the following histologic features: stromal cellularity, cellular atypia, mitosis, border circumscription versus infiltration, and overgrowth of the stromal cells (no epithelium in at least 1 low-power field [×4 objective, ×10 eyepiece]) (Figure 3, C through F). Tan et al²⁰  have provided detailed recommendations on evaluations of stromal cellularity and stromal atypia. The 2019 WHO Classification of Tumours of the Breast, 5th edition¹  also recommends removing well-differentiated liposarcoma from among the malignant heterologous components of malignant PT, since well-differentiated liposarcoma in this setting does not contain the same genetic changes observed in well-differentiated liposarcoma elsewhere and has no metastatic potential.^35,36  Multinucleated stromal giant cells have been seen in PT; Tse et al³⁷  have shown that these cells do not represent a different or more active stromal population.

Periductal stromal tumors (now classified under PT) are also biphasic lesions that show nodular periductal stromal proliferation without the leaflike structures typically seen in PT.³⁸  The border is not well circumscribed, and adjacent nodules can consolidate to form a bigger mass, making the border seem infiltrative.³⁹ 

Pathologic diagnosis and grading of FELs are based on morphologic features, and it is critical to have adequate sampling, especially in larger lesions, as diagnostic features can be very focal. The major differential diagnoses of malignant spindle cell lesions in the breast are metaplastic carcinoma and malignant PT. Most of the time, the diagnosis is straightforward if one can identify areas of classic carcinoma or PT. Sometimes, cytokeratin (CK) markers have to be used to differentiate these 2 lesions.⁴⁰  However, caution must be taken as CK can show focal positivity in malignant PT.^41,42  CD34 often shows positivity for stromal cells in FELs, more so in benign FELs, and it is particularly helpful when differentiating FELs from papillary lesions of the breast.^39,43,44  Immunohistochemistry analysis for c-kit and p53 has been used in some studies to aid in the diagnosis, but it has not been validated for routine clinical use.⁴⁵ 

Breast lesions (benign or malignant) are rare in children and adolescents. Among them, FAs are the most common. However, besides the classic morphology of FAs seen in the adult population, FAs in pediatric patients often show increased stromal cellularity, presence of leaflike structures, and increased stromal mitotic activity; these features can make it difficult to differentiate them from PT at times.⁴⁶  In a previous study, Ross et al⁴⁷  evaluated 11 conventional FAs, 23 juvenile FAs, and 20 PTs (16 benign, 1 borderline, 3 malignant) in pediatric patients (Figure 4, A and B). They described these lesions as having increased stromal cellularity, but no nuclear atypia was identified. Both conventional FA and juvenile FA in pediatric populations can have features overlapping with PT, such as increased stromal mitosis, to a level that overlaps with borderline PT (6 per 10 high-power fields [HPFs] and 7 per 10 HPFs, respectively). Thus, using mitotic activity alone in this age group could be misleading. Ill-formed leaflike structures are also seen more frequently, which can be confused with PT as well.⁴⁸ 

Emerging molecular studies of FELs have highlighted that MED12 mutations, which were first discovered in uterine leiomyoma, are associated with FELs of the breast.^23,49 MED12 mutations are associated with dysregulated estrogen signaling and extracellular matrix organization.⁵⁰  Recurrent MED12 mutations, most at codon 44 of exon 2, were found in both FA and PT, but with higher frequency in FA (about 60%) and lower-grade PT than in higher-grade PT,^5,7  suggesting the presence of MED12 independent pathway. Data regarding clinical outcomes associated with MED12 mutations are few and not conclusive.⁷  Like MED12, mutations in retinoic acid receptor, alpha (RARA) are also found more frequently in FA and benign PT. Variants of FA share similar genetic changes with conventional FA,^51,52  with the exception of myxoid FA,³³  which is not associated with MED12 mutation. MED12 mutation was also not identified in 1 case of periductal stromal tumor in a recent report.⁵³  Besides MED12, borderline and malignant PTs harbor neurofibromin 1 (NF1), retinoblastoma (RB1), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), epidermal growth factor receptor (EGFR), TP53 (p53), and Erb-B2 receptor tyrosine kinase 4 (ERBB4) mutations.⁵⁴  Notably, high stromal telomerase reverse transcriptase (TERT) expression and promoter mutation are associated with malignant PTs, which are also commonly seen in other malignancies, including metaplastic carcinoma.⁵⁵  Thus, MED12 and RARA mutations are more specific and more likely to be useful in the differential diagnosis of FELs.^4,5  Additionally, Sim et al⁶  found that PTs had higher mutation counts than FAs (54.6% versus 8.4%), with no significant difference between benign, borderline, and malignant PTs in their study of 275 FELs.⁶  Interestingly, identical MED12 mutations were observed in both FA and PT from the same patient, suggesting that FA can give rise to PT.⁵⁶  In general, the presence of TERT promoter mutations favors PT over FA.

Molecular findings such as MED12 mutations are present in pediatric FA, similar to those for adult FA.⁵⁷  Tay et al⁵⁸  studied 43 tumors from 35 pediatric patients with an upper age limit of 18 years and none of the tumors harbored TERT promoter mutation. This is particularly helpful in differentiating them from more aggressive PT, since there is often overlapping morphologic properties between these 2 lesions in the pediatric population.

Most FAs do not recur after complete surgical excision. Traditional management options for FA include observation or surgical excision. Peng et al⁵⁹  recommend that young patients with FA have regular follow-up after core needle biopsy confirmation, as the incidence of the malignancy is exceedingly low. However, we should note that the rate at which FA/FEL diagnosed on biopsy is upstaged to PT on excision is 18% to 42%, especially with a diagnosis of cellular FEL in core biopsy.^60–64  These studies suggest that in the absence of definitive preoperative factors, patients should undergo surgical excision with a low threshold, especially with a lesion showing heterogeneous echotexture on ultrasonography or a higher Breast Imaging Reporting and Data System (BI-RADS) score (≥4b). The studies suggest that the surgical risks and cost compared to long-term follow-up would be more beneficial.

Co et al⁶⁵  showed that margin was the only factor associated with recurrence in their cohort of 465 cases of PT between 1998 and 2014. However, recent studies increasingly have shown that the extent of margins and margin width are not associated with the risk of recurrence.^66–68  This may be one of the reasons that many clinicians from different centers do not follow current guidelines, which require wide margins for all PTs.⁶⁹  Tan et al⁷⁰  have suggested that the 1-cm margin should be used only for recurrent PT and malignant PT, while benign/borderline PT can be treated with simple excision. This suggestion was supported by a later study from Cowan et al,⁷¹  which showed that benign and low-grade FELs have low recurrence rate even with positive margins. Ogunbiyi et al⁷²  have proposed an algorithm on how to treat PT surgically. Routine use of postoperative radiation is not recommended but can be considered in cases of local recurrence and malignant PT together with chemotherapy. These recent studies are reflected in recently proposed changes in version 2.2022 of the guidelines from the National Comprehensive Cancer Network for the management of PTs, which recommend wide excision of greater than 1 cm and no axillary staging for borderline/malignant PT and simple excision for benign PT.⁷³ 

Tumor grades have been suggested to be the strong predictor for local recurrence,⁷⁴  as confirmed by a meta-analysis from Lu et al,⁷⁵  who analyzed 54 studies and 9234 cases. Large tumor size, cellular atypia, tumor necrosis, and heterologous differentiation are also associated with poor prognosis and increased risk of relapse.^76,77  A study from Slodkowska et al³⁴  showed that age below 50 years and predominantly myxoid stroma were significant for local recurrence, while age above 50 years, stromal overgrowth, diffuse marked atypia, tumor necrosis, and high mitotic index of at least 10 per 10 HPFs were significant for distant metastasis. Treatment options in actual practice have been widely different from recommended guidelines. More studies are needed to update the current guideline. In the meantime, individual treatment should be carefully planned for each patient. Because the stromal component of PT is neoplastic, the 2019 WHO Classification of Tumours of the Breast¹  recommends that malignant PT be staged as sarcoma, using the Union for International Cancer Control (UICC) TNM classification.⁷⁸ 

Leraas et al⁴⁸  have compared 62 PTs in pediatric patients to 2725 PTs from adult patients and concluded that pediatric patients with PT have a significantly better prognosis than their adult counterparts, again suggesting we should treat this group of patients with caution. Studies to date have shown that pediatric FELs harbor only the MED12 mutation, not the TERT mutation, which further reinforces that despite worrisome morphology and tendency to form large lesions, pediatric FAs have genetic alterations similar to those of adult FAs and should be treated conservatively.

With overlapping pathomorphology and significant management differences in FELs (Table), more data are needed from molecular studies to guide us for a more accurate diagnosis and management of each entity.