Complex Fibroadenoma with Pronounced Squamous Metaplasia: A Rare Case Report,Differential Diagnostic Considerations,and Associated Breast Cancer Risk

Introduction

Complex fibroadenomas are fibroadenomas with associated histologic characteristics, including cysts (≥3 mm), sclerosing adenosis, epithelial calcifications, or papillary apocrine metaplasia. ¹ Although fibroadenomas are found to be present in nearly 10% of women, 70% to 90% of fibroadenomas are simple fibroadenomas with only a small subset classified as complex. Although considered benign breast masses, fibroadenomas carry an increased risk for breast cancer. Complex architecture, however, does not independently convey any increased risk beyond that of simple fibroadenomas when stratified for proliferative diseases without atypia. ¹ Although squamous metaplasia in association with breast carcinomas is well recognized, primary squamous metaplasia is a rare entity in fibroadenomas and the nonneoplastic breast in general. ² In light of the rare nature of extensive squamous metaplasia occurring in a benign complex fibroadenoma, we aim to present a unique case, as well as a discussion of important differential diagnostic considerations when encountering such an entity. We also reviewed the complex fibroadenoma-associated breast cancer risk in our institution.

Case Report and Comparison

A 30-year-old female, G3P2012, with a 2.5 pack-year smoking history presented to the breast care center with a palpable right breast mass for 1.5 years. The patient reported the lesion doubled in size and was intermittently painful during the last 6 months. On physical examination, there was a mobile palpable mass in the medial right breast at ∼2:30 clock position, 3 cm from the nipple. No other lumps/lesions, enlarged lymph nodes, nipple discharge, or skin changes were present on either breast. A mammogram was obtained revealing a high density circumscribed oval mass measuring up to 6 cm (Figure 1A). A further evaluation with targeted ultrasound demonstrated a circumscribed, primarily isoechoic and heterogeneous mass with scattered cystic areas (Figure 1B). The lesion was designated BI-RADS Category 4: suspicious abnormality, with recommendation for ultrasound-guided biopsy.

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Figure 1.

(A) Mammogram: high density circumscribed oval mass in the inner central right breast, up to 6 cm. (B) On targeted ultrasound, there was a circumscribed, primarily isoechoic, heterogeneous mass with scattered cystic areas measuring 6 × 4.6 × 3.3 cm.

An ultrasound-guided biopsy was obtained with 2 tissue cores, which revealed a fibroepithelial lesion most consistent with fibroadenoma with mild epithelial hyperplasia of the usual type, apocrine metaplasia, and squamous metaplasia. The patient opted for immediate surgical removal due to the increased size and pain of the lesion. Surgical excision of the lesion was subsequently performed without complication. The patient has done well in postprocedural follow-up.

Sectioning of the lumpectomy specimen revealed fibroadipose tissue with a tan-white diffusely fibrotic, multifocally cystic lesion, measuring 4 × 3.8 × 2.4 cm. A histologic examination demonstrated a well-circumscribed biphasic lesion with stromal and epithelial proliferation, apocrine metaplasia, multiple cysts, and sclerosing adenosis (Figure 2A). Interestingly, prominent squamous metaplasia forming multiple keratinaceous cysts were identified (Figure 2B). Immunohistochemical stains demonstrated positive staining for pancytokeratin within all epithelial elements. P63 and calponin immunostains (Figure 3) demonstrated preservation of myoepithelial cells around all ductal elements. Additionally, the squamous metaplasia was only positive for p63 but not for calponin, which overall represented ∼20% of the lesion.

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Figure 2.

(A) Complex fibroadenoma featuring fibroepithelial proliferation, adenosis, cyst formation, and apocrine metaplasia. (B) Higher power view of benign squamous metaplasia with anucleated squamous debris.

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Figure 3.

P63 (A) and calponin (B) immunohistochemistry highlighting retention of myoepithelial cells. It has been noted that the squamous metaplasia is only positive for p63.

To place this lesion in the context of our overall patient population, we queried our electronic medical record system (CoPath) for complex fibroadenomas from over the past 20 years (Table 1). Within that time, a total of 23 diagnoses of complex fibroadenoma were made in patients ranging in ages from 29 to 76 years (mean 45 years). Although 2 patients had breast cancer at the time of diagnosis, none of the patients went on to develop breast cancer with an average follow-up of 90 months. In a patient with high-grade invasive ductal carcinoma, the complex fibroadenoma was within the same breast, and the other patient presented with invasive solid papillary carcinoma in the contralateral breast. Although proliferative changes are not a requisite feature of complex fibroadenomas, our cohort included 15 cases with sclerosing adenosis, 2 cases with usual ductal hyperplasia (UDH), and 2 cases with atypical ductal hyperplasia (ADH), suggesting that proliferative changes are common findings. Notably, both patients who presented with cancer in conjunction with a complex fibroadenoma did have proliferative features (sclerosing adenosis, UDH, and/or ADH). These 2 patients were also older than our overall patient average (58 and 76 years). Only 30% (n = 7) of cases presented with metaplastic elements within the lesion. Apocrine metaplasia was the most common, with 7 lesions displaying these changes. There was 1 case showing papillary apocrine metaplasia with mild proliferation. The lesion reported herein had apocrine metaplasia, and additionally, was the only case with squamous metaplasia.

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Table 1.

A 20-Year Complex Fibroadenoma Retrospective Review Findings.

Total	23 cases
Age	29-76-year-old (mean 45 years)
Proliferative changes	Sclerosing adenosis (15 cases) UDH (2 cases) ADH (2 cases)
Metaplastic changes	Apocrine metaplasia (7 cases) Squamous metaplasia (1 case)
Breast cancer at the time of diagnosis	2 cases
Breast cancer during follow-up	0 cases
Follow-up time	90 months (mean)

Note: It should be noted that 1 case contained papillary apocrine metaplasia with mild epithelial proliferation.

Abbreviations: UDH: usual ductal hyperplasia; ADH: atypical ductal hyperplasia

Discussion

Fibroadenomas are the most common benign breast tumor in young women. Histologically, it is a benign biphasic tumor with epithelial and stromal components. The glandular epithelial elements are composed of tubules lined by cuboidal or low columnar elements resting on a myoepithelial layer. The tubules are often compressed by a stromal proliferation of fibroblasts in a dense fibrous stroma. The cellularly of the stroma varies from case to case but is not unduly hypercellular. ³

Complex fibroadenomas contain the above features in addition to one of the following: sclerosing adenosis, cysts >3 mm, papillary apocrine metaplasia, and/or epithelial calcifications. Although some literature has reported an even higher increased risk of breast cancer in the setting of complex fibroadenomas over the usual type fibroadenomas (2.17 times increased risk vs 3.10 in complex), ⁴ more recent data has ascribed the increased risk to the proliferative change, which may or may not be present, in the complex fibroadenomas. ¹ Because this subtype is more often seen in association with proliferative disease, it has a slightly higher risk than conventional fibroadenomas. Our data also suggests that proliferation is a common finding in complex fibroadenoma and supports the conclusion from the Mayo Clinic Benign Breast Disease Cohort Study. ¹ More importantly, in the patient population with an average 90 months follow-up, there were no incidences of developing cancer after a diagnosis of complex fibroadenoma. Metaplasias represented a less frequently encountered finding. Our cohort had 7 cases with apocrine metaplasia, and only 1 case had squamous metaplasia.

Complex fibroadenomas are a rare subtype of a common breast lesion, and as demonstrated in our case review, squamous metaplasia is exceedingly rare in this setting, as well as in nonneoplastic breast in general. ² As treatment and surgical planning rely heavily on biopsies, it is important that pathologists are aware of this possibility, in addition to the other array of benign causes of squamous metaplasia, such as a previous biopsy site or breast implant capsule. Squamous metaplasia of the lactiferous ducts (SMOLD), intraductal papillomas with squamous change, and response to trauma are other considerations.

SMOLD (otherwise known as Zuska disease or recurrent subareolar abscess) is a result of lactiferous ductal squamous epithelium extending too far from the surface. Keratinizing squamous epithelium found at the nipple normally invaginates into the nipple duct for ∼1 to 2 mm. However, if the squamous epithelium extends further, keratin may accumulate and cause duct obstruction and cystic dilation. Rupture of the duct wall will result in the extrusion of keratinous debris, eliciting a foreign body giant cell inflammatory reaction. ⁵ SMOLD is usually located superficially and associated with smoking. Although our patient had a 10-year history of smoking (2.5 pack-years), the squamous metaplasia was deep-seated with little to mild inflammation and in association with a complex fibroadenoma.

Intraductal papilloma with a prominent squamous change has also been reported.^6-8 Reddick et al ⁶ demonstrated by electron microscopy and immunohistochemistry that the squamous differentiation originated from myoepithelial cells. Primary squamous metaplasia arising in nonneoplastic breast parenchyma has been rarely reported and is generally associated with trauma.^9,10 Mills and Daniel ⁹ suggested an epithelial origin for the primary squamous metaplasia. Histologically, posttraumatic lobular squamous metaplasia of the breast bore a striking resemblance to squamous sialometaplasia of the salivary gland in that it exhibited lobular, pseudocarcinomatous growth. ¹⁰

Squamous metaplasia occurring in adenocarcinoma of the breast is well recognized, and if present should prompt careful examination for an underlying adenocarcinomatous component. Squamous differentiation can also be seen in metaplastic carcinoma. Metaplastic carcinoma—which comprises <1% of invasive breast carcinomas—is a heterogeneous group of malignant tumors in which all or part of the carcinomatous glandular epithelium is transformed into a nonglandular (metaplastic) growth process. ¹¹ Descriptive diagnostic categories of metaplastic carcinoma include squamous cell carcinoma, metaplastic carcinoma with mesenchymal differentiation, low-grade adenosquamous carcinoma, spindle cell carcinoma, and fibromatosis-like metaplastic carcinoma. Metaplastic carcinomas with squamous differentiation can range from well to poorly differentiated, and in up to two-thirds of cases there is prominent cystic degeneration with central necrosis. ¹² The squamous epithelial-lined cysts may often resemble benign epidermal inclusion cysts. Nests of malignant squamous cells may also be present in the adjacent breast stroma. ¹³ Pure squamous cell carcinoma of the breast without any identifiable component of adenocarcinoma is exceedingly rare and may originate from the skin, nipple, epithelium of a deep-seated dermoid cyst, or squamous metaplasia on a chronic inflammatory background. ¹²

Another malignant diagnostic consideration is the phyllodes tumor. Although only a small proportion of phyllodes tumors are classified as borderline or malignant, squamous metaplasia has rarely been described to occur.^14,15 Phyllodes tumors have the histologic configuration of fibroadenomas, but with hypercellular stroma. The degree of nuclear atypia, mitosis per high power fields, stromal overgrowth, and heterologous elements aid in the classification of malignant potential. ³

Squamous metaplasia can present in the breast following surgery and radiation for breast cancer. Although this is a rare condition, it is very important to recognize since there is a potential to misinterpret radiation atypia as recurrent breast cancer. Saad et al ¹⁶ reported 2 patients with squamous metaplasia in the breast following lumpectomy and radiation therapy. Both showed cytologic atypia due to the previous radiation. One patient went on to have a mastectomy and the other patient had several biopsies, which all showed no evidence of malignancy. A history of radiation along with the cytologic recognition of radiation effect can assist in avoiding false-positive diagnoses.

Conclusion

Squamous metaplasia in the breast is an unusual finding, and practicing anatomic pathologists should keep the array of benign and malignant differentials in mind. Complex fibroadenomas are often associated with proliferative lesions, and the increased risk for developing breast cancer might be due to the proliferative conditions.