Fibroepithelial Neoplasms



Fibroepithelial Neoplasms


Edi Brogi



SCLEROSING LOBULAR HYPERPLASIA (FIBROADENOMATOID MASTOPATHY)


Clinical Presentation

Sclerosing lobular hyperplasia (SLH) occasionally forms a localized tumor (1,2) and may be associated with tenderness.


Age

Patient age ranges from 12 (3) to 46 (4) years, with a mean age of about 32 years. There is no significant association with oral contraceptive use.


Radiology

The imaging findings closely resemble those of fibroadenoma (FA). Calcifications may be present.


Microscopic Pathology

The lobules are enlarged, with an increased number of acini. The intralobular stroma is collagenized, with variable levels of sclerosis (Fig. 7.1). Adjacent lobules appear as minute FAs with a prominent glandular component (Fig. 7.2). The acini are lined by monostratified epithelium, and myoepithelial cells are evident. Secretory activity may be present. Calcifications are uncommon. SLH can occur near FAs and phyllodes tumors (PTs) (1,5).


Treatment and Prognosis

SLH is a benign alteration of the breast parenchyma and does not require any specific treatment. Surgical excision might be considered if the needle core biopsy (NCB) sampling from a breast mass yields only SLH to rule out peripheral/inadequate sampling of a PT. Clinical and radiological correlation is necessary.


FIBROADENOMA


Clinical Presentation


Age

FAs with usual/adult-type morphology can occur at any age, but the median age at diagnosis ranges from 30 to 40 years, approximately 10 to 20 years lower than the median age of patients with PTs. Juvenile FAs tend to occur in girls younger than 20 years old and are the most common fibroepithelial lesions in pediatric patients (6,7). Fibroepithelial lesions with the histologic features of juvenile FA also occur in adult women (8). Complex FAs tend to occur at an older age than adult FAs. The mean age at diagnosis was 34.5 years in one study (9). In another series (10), the median age of patients with complex FA was significantly higher than the median age of patients with noncomplex FAs (47 years vs. 28.5 years, respectively).


Risk Factors

Some studies have suggested a relationship with hormonal treatment. Some FAs develop during puberty after menarche (6). The familial occurrence of multiple successive FAs has been observed. Rare examples of FAs are reported in men (11,12,13,14,15), usually in the context of gynecomastia.

Women treated with cyclosporin A for immunosuppression may develop large, multiple, and bilateral FAs (16,17). The duration of cyclosporin A treatment prior to the detection of a FA is generally more than a year (17). Some FAs regressed completely after cyclosporin was replaced with another immunosuppressive drug, whereas other FAs remained stable or decreased in size (18).

Women with Carney syndrome may develop myxoid FAs (19). The percentage of women with myxoid FA who have Carney syndrome is unknown.



Radiology

An increasing percentage of FAs are nonpalpable tumors detected by mammography as discrete nodular densities. Mammographic calcifications in the stroma of adult FAs are common in postmenopausal women. By ultrasound examination, most FAs are nodular, iso- or hypo-echoic solid masses with circumscribed borders. In one study (20), myxoid FAs showed significantly greater depth-to-width ratio than usual FAs, and some were suspicious for mucinous carcinoma. The MRI appearance of FAs is variable and influenced by the structure and relative proportions of epithelial and stromal
components. In an MRI study of 81 FAs (21), 70.4% had well-defined margins, 90.1% were round or lobulated, 49.4% had heterogeneous internal structure, and 27.2% displayed nonenhancing internal septations. After contrast injection, 22.2% of FAs had a suspicious signal intensity-time course.






FIGURE 7.1 Fibroadenomatoid Mastopathy. A, B: This needle core biopsy specimen was obtained from one of multiple bilateral breast nodules in a 16-year-old girl. The biopsy specimen shows enlarged lobules with sclerotic stroma.


Size

Most FAs are smaller than 3 cm. FAs larger than 4 cm are more frequent in patients under 20 years of age (22), and usually have morphology of juvenile FA. The so-called “giant” FA (a descriptive term that we do not endorse) in the breast of adolescent girls often has the morphology of juvenile FA. The mean size of 23 juvenile FAs in women 18-years-old or younger studied by Ross et al. (6) was 3.1 cm (range 0.5-7). In one series (10), the average size of complex FAs (1.3 ± 0.57 cm) was about half the size of usual FAs in the same study (2.5 ± 1.44 cm).


Microscopic Pathology

FA is a tumor of the specialized mammary stroma, associated with a secondary proliferation of the glandular elements. The stroma shows either intra- or pericanalicular growth pattern (Fig. 7.3). FAs with a prominent intracanalicular pattern can mimic benign PTs, especially in NCB samples. Within any given FA, the stroma has homogeneous cellularity, and the epithelium-to-stroma ratio is similar throughout the tumor (Fig. 7.3). In contrast, PTs have an uneven distribution of glands and heterogeneous stromal cellularity, including foci indistinguishable from a FA. Adipocytic differentiation does not occur in FAs, but it may occur in PTs.






FIGURE 7.2 Fibroadenomatoid Mastopathy. The lobules resemble small fibroadenomas.

Multinucleated stromal giant cells can be found in FAs (23) and PTs (23), in some benign breast tumors (24), as well as in nonlesional mammary stroma. The nuclei may be pleomorphic and hyperchromatic, or have a florette-like pattern. The presence of multinucleated stromal cells does not appear to influence the clinical course of the lesion. FAs with focal multinucleated stromal giant cells should not be misclassified as PTs, even if the cells are focally p53- and Ki67-positive (24).

The usual (adult-type) FA is the most common type of FA (Fig. 7.4). Usual FAs in postmenopausal women tend to be hypocellular and hyalinized, and they may harbor coarse dystrophic stromal calcifications (Fig. 7.5). FAs from women younger than 20 years of age usually have more cellular stroma. Epithelial hyperplasia is usually absent; focal secretory changes may be present (Fig. 7.6). Mitotic figures are uncommon in usual FAs, but scattered mitoses may be observed in usual FAs in adolescent girls (6,7).

A tubular adenoma is a variant of pericanalicular FA with adenosis (Fig. 7.7). It consists of closely approximated round or oval glandular structures lined by monostratified glandular epithelium and myoepithelium.

An adult-type FA with cellular stroma but no cytologic atypia is often referred to as cellular FA, but this diagnosis has low interobserver reproducibility. The differential diagnosis between cellular FA and benign PT can be problematic, especially if only NCB material is available for review (Figs. 7.8 and 7.9); surgical excision of the lesion is warranted for its definitive classification. Usual FAs rarely pose a diagnostic challenge in NCB material. A hyalinized FA with conspicuous epithelium may occasionally raise the differential diagnosis of a sclerosed papilloma, but the pseudopapillary fronds lack true fibrovascular cores.







FIGURE 7.3 Fibroadenomatous Growth Patterns. A: The intracanalicular growth pattern is formed by compressed epithelial lined spaces. B: A pericanalicular lesion in which the stroma is arranged in a circumferential nodular pattern around ductules with focal epithelial hyperplasia.






FIGURE 7.4 Fibroadenoma, Usual Type. This needle core biopsy specimen is from a palpable lesion in a 37-year-old woman.






FIGURE 7.5 Fibroadenoma, Usual Type with Sclerosis and Calcification. A, B: This needle core biopsy specimen is from a nonpalpable, calcified lesion in a 74-year-old woman.







FIGURE 7.6 Fibroadenoma, Usual Type with Secretory Changes. This needle core biopsy specimen is from a palpable lesion in a 32-year-old woman. The patient is a BRCA1 germline mutation carrier, and the lesion was suspicious clinically.






FIGURE 7.7 Lactating Adenoma. A, B: Enlarged lobules with lactational secretory hyperplasia in needle core biopsy samples from a breast tumor in a 37-year-old pregnant woman.






FIGURE 7.8 Fibroepithelial Lesion. A, B: The stroma of the fibroepithelial lesion in this needle core biopsy sample shows minimally increased cellularity with no evidence of cytologic atypia. The ducts are open and have a clefted outline, but no epithelial hyperplasia is present. Some of the features (cellularity and clefts) raise the differential diagnosis of benign PT. Surgical excision of the lesion yielded a fibroadenoma.







FIGURE 7.9 Fibroepithelial Lesion. A: The stroma of the fibroepithelial lesion in this needle core biopsy sample shows increased cellularity with no definitive evidence of cytologic atypia. A duct is lined by hyperplastic epithelium. Within the duct lumen are small detached and round fragments of stroma lined by epithelium all around, in a frond-like arrangement. Some of the features (cellularity, epithelial hyperplasia, and small fronds) raise the possibility of benign PT. Surgical excision of the lesion confirmed the latter diagnosis. B, C: This needle core biopsy sample shows a fibroepithelial tumor with moderately cellular stroma that proved to be a benign phyllodes tumor. D, E: These needle core biopsy samples are from a benign phyllodes tumor, a diagnosis suggested by the moderately cellular stroma and epithelium-lined clefts.

The underlying architecture of an infarcted FA can usually be identified in H&E-stained sections and can be highlighted with CK stains (Fig. 7.10).

Myxoid FAs are characterized by diffuse and homogenous myxoid change of the stroma (Fig. 7.11). Myxoid FAs can occur in patients with Carney syndrome (19), but most patients with a myxoid FA do not have a known systemic abnormality. Myxoid FAs have uniformly hypocellular stroma with evident vascularity, whereas myxoid change in a PT tends to be less homogeneous, and stromal cellularity is increased. The differential diagnosis of myxoid FA in NCB specimens includes mucinous carcinoma (Fig. 7.12) and PT with focal myxoid stroma.

Complex FAs are FAs with at least one of the following histologic features: sclerosing adenosis (SA), papillary apocrine hyperplasia, cysts (≥3 mm), and epithelial calcifications (Fig. 7.13) (9,25). In a series of 63 complex FAs (10), 57% had SA, 8% had apocrine metaplasia, and 1.6% had cysts. Calcifications in SA were found in 9.5% of the cases. Fibrocystic changes (FCCs) such as papillary epithelial hyperplasia and SA can mask the basic fibroadenomatous nature of a complex



FA, especially in the limited sample of a NCB, and raise the differential diagnosis of FCCs (Fig. 7.13), juvenile papillomatosis, and papilloma (Fig. 7.14). The differential diagnosis of complex FAs with extensive SA also includes invasive carcinoma (Fig. 7.15). Surgical excision of a complex FA is not necessary, unless the epithelium shows evidence of atypia or the diagnosis is uncertain.






FIGURE 7.10 Infarcted Fibroadenoma. A: This needle core biopsy of a palpable lesion in the breast of a 15-year-old girl had been initially interpreted as a vascular lesion, but the ghostly outline of the tissue suggests an infarcted fibroadenoma. B: A cytokeratin 7 stain highlights the necrotic epithelium, confirming that the lesion is an infarcted fibroadenoma, not a hemangioma.






FIGURE 7.11 Fibroadenomas with Myxoid Stroma. A: A needle core biopsy sample showing myxoid stroma in a fibroadenoma. B, C: Needle core biopsy specimens in which the epithelium is compressed into slender cords and small glands by myxoid stroma.






FIGURE 7.12 Fibroadenoma with Myxoid Stroma. A, B: A needle core biopsy sample showing myxoid stroma in a fibroadenoma. This lesion had been misinterpreted as mucinous carcinoma.






FIGURE 7.13 Complex Fibroadenoma. A, B: A needle core biopsy sample showing a complex fibroadenoma with apocrine cysts and adenosis.






FIGURE 7.14 Complex Fibroadenoma. This complex fibroadenoma has foci with a papillary appearance that could raise the differential diagnosis of papilloma in a needle core biopsy sample.






FIGURE 7.15 Complex Fibroadenomas with Sclerosing Adenosis Misinterpreted as Carcinoma. A, B: A needle core biopsy specimen showing sclerosing adenosis in a fibroadenoma. This specimen was erroneously interpreted as infiltrating lobular carcinoma. C, D: This needle core biopsy specimen with sclerosing adenosis in a fibroadenoma was diagnosed as invasive tubular carcinoma. E, F: The needle core biopsy of this complex fibroadenoma with adenosis raises the differential diagnosis of invasive carcinoma. A stromal lymphocytic infiltrate is also noted (arrow in F).






FIGURE 7.16 Juvenile Fibroadenoma. A: The needle core biopsy of a large palpable mass in the breast of a 15-year-old girl shows a fibroepithelial lesion with slightly increased stromal cellularity, adenosis, and mild epithelial hyperplasia. B: Surgical excision of the mass yielded a juvenile fibroadenoma.

A juvenile fibroadenoma is characterized microscopically by increased stromal cellularity and epithelial hyperplasia. Pericanalicular architecture is more common than intracanalicular architecture (6,7). The tumor border is well defined. The stroma tends to be uniformly cellular, with scant separation between intralobular/periglandular stroma and interlobular stroma (6). The glandular element tends to be uniformly distributed, but some juvenile FAs can show slight stromal expansion as well as gland-rich areas (6), creating an overall impression of intratumoral heterogeneity that might raise the differential diagnosis of PT, especially on review of NCB material. The uniform quality of the stromal proliferation and lack of nuclear stromal atypia are features that support the diagnosis of FA. Epithelial hyperplasia is common in juvenile FAs and can be conspicuous, raising the differential diagnosis of atypical ductal hyperplasia (ADH) or cribriform ductal carcinoma in situ (DCIS), which are exceedingly rare in this setting. Necrosis and/or calcifications are uncommon. A definitive diagnosis of juvenile FA cannot be rendered based on review of NCB material alone (Fig. 7.16). Evaluation of the entire lesion is necessary. The differential diagnosis usually includes benign PT and papilloma. The epithelial hyperplasia in a juvenile FA may raise the differential diagnosis of ADH if the presence of the underlying stromal lesion is not appreciated, especially in NCB material.


Fibroadenoma with Carcinoma In Situ or Epithelial Atypia

LCIS and DCIS can arise within or secondarily involve FAs. Classic LCIS and ALH (Fig. 7.17) are the most common atypical epithelial proliferations found in FAs; pleomorphic LCIS is exceedingly rare. Occasionally, ADH and DCIS (Fig. 7.17) are identified (26,27). The differential diagnosis of ADH in FA includes artifactual telescoping of the benign epithelium in the FA (Fig. 7.18). A FA may be involved by invasive carcinoma arising in the adjacent breast parenchyma.


Immunohistochemistry

The epithelium and stroma of FAs show some positivity for ER and PR, but these findings have no specific diagnostic applications. The stromal cells of FAs are CD34-positive and show immunoreactivity for actin in cases with myofibroblastic proliferation. Moderate-to-strong nuclear staining for β-catenin has been documented in the stroma cells of FAs (28). A few investigators have reported significant differences in the Ki67 indices of FAs and benign PTs in NCB (29,30), but substantial overlap exists, limiting the practical utility of this marker in the evaluation of NCB specimens.


Treatment and Prognosis

Recent molecular studies suggest that some PTs might develop from FAs (31,32,33), but this occurrence is exceedingly rare. Correlation of the clinical, radiologic, and pathologic findings of the lesion is of foremost importance. In the absence of atypical findings, surgical excision is not warranted for radiologic-pathologic concordant lesions yielding the diagnosis of FA at NCB.


Ultrasound-guided Vacuum-assisted Percutaneous Excision

Small (≤1.5 cm) FAs can be completely excised in the course of vacuum-assisted, ultrasound-guided biopsy (34,35). In a series of 52 FAs (35) removed percutaneously under sonographic guidance, and followed up with clinical and sonographic examination every 6 months, the recurrence rate was 15% at a median follow-up of 22 months (range 7-59), with an actuarial recurrence rate of 33% at 59 months. None of the recurrent lesions
was symptomatic, and only three were palpable. All recurrences pertained to FAs ≥2 cm at initial diagnosis (range 2.1-2.8).






FIGURE 7.17 Fibroadenomas with Epithelial Atypia or Carcinoma In Situ. A, B: The complex fibroadenoma in this needle core biopsy sample has an area of lobular carcinoma in situ (arrows) and a minute focus of atypical ductal hyperplasia (arrowhead). C: Intraductal carcinoma is present in this sclerotic fibroadenoma.






FIGURE 7.18 Fibroadenoma with Telescoping of the Epithelium. A, B: The ductal epithelium in this fibroadenoma is detached from the duct wall and shows “telescoping” within the ductal lumen, in a pattern that simulates atypical ductal hyperplasia.


Cryoablation

Cryoablation has been used for treating FAs (36,37,38). The mean pretreatment tumor diameter of 444 FAs treated with cryoablation was 1.8 cm (37). A palpable abnormality was present in 46% of patients at 6 months’ follow-up and in 35% at 12 months. In two other series (37,38), a persistent palpable abnormality was more common if the index FA was ≥2 cm. The residual lesion consisted of shrunken hyaline matrix in two cases with tissue evaluation (38).


Surgical Excision

Most solitary FAs are treated by local excision. Excision of juvenile FAs in adolescent patients is usually carried out to
preserve as much breast tissue as possible. The risk of upgrade to carcinoma (DCIS and/or invasive carcinoma) at surgical excision following radiologic-pathologic concordant NCB diagnosis of FA with any morphology is negligible.


Follow-up without Excision

Some patients with radiologic-pathologic concordant NCB diagnosis of FA do not undergo surgical excision of the radiologic target. Semiannual clinical and mammographic follow-up to document stability of the lesion is usually recommended. Features that raise concern for PT include increasing size of the tumor, size larger than 3 cm in a patient older than 35 years, lobulated mammographic contour, and ultrasonographic examination showing attenuation or cystic areas in a solid mass (39).


Relative Risk of Subsequent Carcinoma

The Relative Risk (RR) of subsequent carcinoma in women with FA is minimally increased, even in patients with proliferative changes in the FA or in the surrounding breast, as well as a family history of breast carcinoma (25). Proliferative FCCs are more common within/near complex FAs than noncomplex FAs. In one study (25), the RR of invasive carcinoma for women with any type of FAs was 1.6, but it was 2.4 for women with complex FA, and 3.72 for women with a complex FA and a family history of breast carcinoma. Follow-up information of patients with juvenile FAs is limited but does not reveal predisposition to develop carcinoma (6,7). Some FAs may recur after excision, especially juvenile FAs with more than 2 mitoses per 10 high power fields (HPFs) (7).

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Nov 17, 2018 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Fibroepithelial Neoplasms
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